Towards just transition in Africa: Green financing for urban energy solutions and job creation 9 June 2022 — 7:30AM TO 11:00AM Anonymous (not verified) 18 May 2022 Nairobi and online

This event explores the major openings and potential impediments to the development of a just transition policy in Africa.

Global climate policies towards a ‘just transition’ under the Paris Agreement should also align with and support African states’ national sustainable development priorities. In particular, the need for decent and fair job creation and the establishment of sufficient, resilient and sustainable power supply, accessible to all, and efficient energy use.

Achieving green growth requires innovative and more accessible financing models, especially as wealthy nations’ financial pledges have fallen short. Ahead of the ‘African COP27’ set to take place in Egypt in November 2022, there is a need for transformational strategic thinking and context-specific action from African governments, civil society, businesses and financiers in their green financing demands and national implementation plans.

Sustainable urban energy solutions represent a critical zone of opportunity for the development of new and more reliable green finance pathways. Africa’s rapidly expanding cities present a significant economic opportunity and source of growth. However, urban centres are also where income and energy inequalities are at their starkest. The acceleration of sustainable energy generation and use could have a transformative impact on SMEs and livelihoods across value chains.

At this event, participants will discuss the major openings and potential impediments to the development of a credible ‘just transition’ policy in Africa towards net zero goals, with a particular focus on establishing and enhancing links between green financing innovation, employment creation, sustainable power supply and generation, and sustainable energy usage and consumption in an urban environment.

This event is held in partnership with the Pan African Climate Justice Alliance (PACJA). It is part of a series on Towards Just Transition: Connecting Green Financing and Sustainable Job Creation in Africa, supported by the Chatham House Sustainability Accelerator.

This event will be held in English and French with simultaneous interpretation.

What will authorizing the return of US troops mean for Somalia? Explainer Video aboudiaf.drupal 17 June 2022

Ahmed Soliman examines what the reintroduction of US military means for Somalia.

He says the strategy remains to try and reduce al-Shabaab’s threat, suppress its ability to carry out operations, and target its senior leadership.

There is more of a recognition now that the focus needs to be on restoring an effective security sector within Somalia and ensuring their forces are ready, but this also requires better coordination between the federal government and federal member states which it is hoped will happen in this new administration.

Towards just transition in Africa: Green financing for nature-based solutions and rural resilience 21 July 2022 — 9:30AM TO 1:00PM Anonymous (not verified) 30 June 2022 Libreville and online

This hybrid event in Libreville explores just transition policy and green financing for nature-based solutions, with a particular focus on the integration of job creation priorities in conservation and rural resilience.

Global climate policies towards a ‘just transition’ under the Paris Agreement should align with and support African states’ national sustainable development priorities – in particular, the need for decent and fair job creation, as well as resilient and sustainable land, environment, and ecosystem management policies.

Achieving green growth requires innovative and more accessible financing models, especially as wealthy nations’ financial pledges have fallen short. Ahead of the ‘African COP27’ set to take place in Egypt in November 2022, there is a need for transformational strategic thinking and context-specific action from African governments, civil society, businesses and financiers, in their green financing demands and national implementation plans.

Preservation of biodiversity and nature is not only critical in the global fight against climate change but is also vital for conservation-based economic development. Natural capital stocks, such as terrestrial and marine ecosystems and biodiversity, produce benefits that support societal and individual well-being and economic prosperity, such as clean air, fresh water, regulation of water flows and pollination of crops – while also acting as important carbon sinks. Financing environmental protection must go beyond compensation and contribute to creating fair social and economic conditions for incentivizing conservation.

At this hybrid event in Libreville, participants will discuss green financing for nature-based solutions, particularly the integration of plans for job creation in conservation and rural resilience within just transition planning.

This event is part of a series on Towards Just Transition: Connecting Green Financing and Sustainable Job Creation in Africa, supported by the Chatham House Sustainability Accelerator.

This event will be held in French and English with simultaneous interpretation.

This event will also be broadcast live on the Chatham House Africa Programme’s Facebook page.

Climbing out of the Chinese debt trap The World Today mhiggins.drupal 1 August 2022

Beijing must play a pivotal role in soothing African economic distress, says Alex Vines.

Poorer countries across the world – including many in Africa – are facing $35 billion in debt-service payments in 2022. According to the World Bank, around 40 per cent of this total is owed to China.

Across the African continent, the economic impacts of the coronavirus pandemic have increased rates of extreme poverty and inequality. Since early 2022 the situation has worsened even further, due to the knock-on effects of spiking inflation and interest rates following the Russian invasion of Ukraine. Shortages of fuel and foodstuffs have caused prices to leap upwards. Urban unrest is on the rise, and African governments are having to make tough economic choices as their budgets are squeezed ever more tightly.

Across the continent, progress on the UN’s Sustainable Development Goals is being jeopardized, and non-energy-producing lower and lower-middle income African governments are struggling to repay their loans.

During the Covid pandemic, the G20 assisted 31 out of 36 eligible African countries with its Debt Service Suspension Initiative (DSSI). Established in May 2020, the DSSI helped countries concentrate their resources on fighting the pandemic and safeguarding the lives and livelihoods of millions of the most vulnerable people before it expired at the end of 2021. From 2022, it has been replaced by the G20’s Common Framework for Debt Treatments.

As the second-largest economy in the world after the United States, and the dominant lender for many African states, China has an important role to play in such initiatives. Beijing still tries to keep a low profile and renegotiate its terms on a bilateral basis – although it did support Angola’s early call for G20 action on an initiative that would fulfil what the DSSI delivered. The challenge is to encourage more consistency and trust in such initiatives, as Chinese officials consider them to be too western-oriented. 
 

China’s lending to Africa peaked in 2016

Contemporary views of Chinese lending in Africa remain coloured by the rapid expansion of Chinese finance from the early 2000s to resource-rich African states, and oil producers in particular. The reality is that much of China’s lending has evolved, and is neither intrinsically predatory nor problematic for African partners – and China increasingly prefers to do business with states it considers to be better run.

In fact, as commodity prices and growth rates declined from 2015, Chinese lending to Africa fell significantly, from a peak of $29.5 billion in 2016 to $7.6 billion in 2019. The socio-economic impact of the pandemic has made this situation worse.

That China has attracted criticism is often due to a lack of transparency in its investments, especially those in Kenya and Zambia. This reputation has not been helped by opaque lending arrangements imposed by Chinese state-owned banks, requiring borrowers to prioritize them for repayment. This could lead to cutbacks in key areas of social spending, with direct impacts on African communities.

Over the past two decades, Chinese finance has contributed to an infrastructure boom in many African countries. Angola, for example, was able to undertake a rapid post-conflict reconstruction of its infrastructure, with new roads and bridges being built across the country. New models of financing are being developed: in Kenya, the new Nairobi expressway was constructed under a $600 million Build-Operate-Transfer model that provides for ownership to revert to the national government after a 30-year concession period.

Chinese companies have helped African countries build and upgrade over 10,000km of railway, around 100,000km of highway, 1,000 bridges and 100 ports, as well as power plants, hospitals and schools.

China’s involvement in African debt has varied considerably between countries and over time. Although in recent years this involvement has been framed in the context of the Belt and Road Initiative, it has for the most part been uncoordinated and unplanned, with credit being offered by competing lenders with links to different elements of the Chinese state.

In recent years, as reports have emerged around the poor quality of some of China’s past lending, the authorities in Beijing have sought greater control over new development lending and have imposed new sustainability requirements. At the same time, African countries have sought to diversify sources of supply for infrastructure contracts beyond China. Loans are generally now on a smaller, more manageable scale.

With the introduction of its Global Development Initiative in September 2021, there are indications that China is moving to a ‘new development paradigm’, with the emphasis on providing flows of foreign direct investment rather than loans and a focus on supporting small and medium-sized enterprises, human capital investments and green development.
 

African debt distress

A paper drawing on expertise from Chatham House’s Africa, Asia and Global Economy and Finance experts will be published before the G20 summit in Bali in November 2022. It examines seven African countries that the World Bank deemed in 2020 to be in most debt distress or at risk of debt distress because of their Chinese stock – Angola, Cameroon, Republic of Congo, Djibouti, Ethiopia, Kenya and Zambia. Two countries – Côte d’Ivoire and South Africa – have received new loans from China and are not in any distress.

The paper observes that a lack of transparency over the nature of the terms agreed by these African governments has led to intense domestic criticism and international accusations that China is seeking control over strategic assets.

In fact, in Angola and Zambia, China may have accidently fallen into its own debt trap through profligate and uncoordinated lending.

Zambia became the first pandemic-era default in 2020 and is seeking relief on $17 billion of external debt. After holding general elections in August 2022, Angola and Kenya will also seek additional debt relief, but both may also seek more funds from the private commercial market because of the slow progress of the G20’s Common Framework – something flagged as a concern by China.

All seven of the countries that are most indebted to China are actively seeking to reduce this financial reliance on Beijing in the future.

China has a pivotal role to play in finding effective solutions to these and other African countries’ debt distress. Improved coordination and cooperation between creditors in China and in other parts the world could enhance the positive impact of multilateral initiatives, such as the Common Framework, which has aimed to bring China and India to the negotiating table along with the IMF, the Paris Club group of creditor nations and private creditors.

So far, Chad, Ethiopia and Zambia are the only African countries to have signed up to the framework since its launch in 2020. Although China is suspicious of the IMF, if African states collectively encouraged Beijing to engage with the Common Framework, it could be improved so as to provide debt relief to those African countries finding it difficult to repay their loans.

Youth innovation can help shape the future of African cities Expert comment LToremark 16 August 2022

To meet the challenges of rapid urbanization, African governments must harness the potential of young innovators to help shape the future of African cities.

It is projected that 1.3 billion people will be living in Africa’s cities by 2050, an increase of almost 1 billion from today, and largely driven by young people migrating to urban centres in search of work. As the continent’s urban population grows, cities will need to adapt by nurturing new economic ecosystems to create jobs, while managing the environmental, social and political pressures that urbanization brings.

The evolution of Africa’s cities is critical for meeting the demands of its youth population and must be co-created with them. Africa’s young innovators are already proving to be an asset in shaping the future of African cities and, if they are allowed to flourish, they could be at the forefront of finding much-needed solutions to the continent’s vast urban challenges.

Growing tech hubs

African countries are increasingly benefitting from growth in technology ecosystems, which are often clustered within cities. There are currently more than 600 tech hubs helping to incubate innovative solutions across cities in Africa. Between 2015 and 2020, the number of start-ups receiving funding grew six times faster than the global average. In 2021 alone, start-ups raised over $4billion in funding – twice as much as in 2020.

But significant challenges remain. While the number of new start-ups is an encouraging indication of the entrepreneurialism and creativity of Africa’s youth, job creation on the level required will demand that they grow and scale up to generate more and higher quality jobs. Research on scaling up in Africa is sparse but research by Endeavor suggests that in Nairobi – one of Africa’s top tech ecosystems – only 5 per cent of companies are able to sustain growth of 20 per cent or more each year, yet they created 72 per cent of new jobs in the previous three years. For Africa to fully harness the potential of digital innovation, making cities the best place for young people to launch ideas and grow them into thriving businesses must become a priority policy for African governments. 

Barriers to scale

On the most basic level, business growth needs access to the services that make cities more liveable and help both urban residents and firms become more productive, such as healthcare, transport, water and sanitation. African cities already struggle to provide their residents – in particular the poorest and most vulnerable – with equitable, reliable, affordable and quality access to these services, in a sustainable manner. And these challenges will only get more acute as urban populations rise rapidly, often without any kind of integrated planning.

For example, an estimated 70-80 per cent of municipal solid waste in Africa is recyclable, yet only about 4 per cent is currently recycled, with more than 90 per cent of waste ending up in uncontrolled dumpsites and landfills. As Africa’s urban population grows, these conditions are likely to worsen – unless there is urgent action. New technology has the potential to help by creating a positive feedback loop between innovation, service delivery and growth. For example, to bridge the waste management gap, innovators are exploring various tech-enabled circular economy models. These solutions are often ground-breaking and have the potential to leapfrog traditional waste management infrastructure. Crucially, they are also formalizing a largely informal sector and creating new jobs.

Across the continent, start-ups like Kaltani, Mr Green Africa and Freetown Waste Transformers build processing facilities to turn waste into energy or reusable products, such as construction materials. Others, like Scrapays, Regenize and Soso Care, are helping households and businesses sell off their recycled materials for cash and virtual currencies or exchange them for critical services, such as micro health insurance premiums. Such start-ups help empower informal waste pickers or agents with tech-enabled tools and target low-income urban communities that would not normally prioritize recycling.

Help or hindrance from the top?

But Africa’s young people cannot do this alone – government decision-makers must become catalysts for entrepreneurial leadership. This requires nurturing a mindset that sees young innovators as Africa’s biggest resource, not a threat. While the importance of young people to Africa’s development is acknowledged in various high-level regional treaties, patterns of inhibition and outright hostility from political ‘elites’ suggest that the disruptive nature of technology start-ups and their access to significant capital through venture capital funding models – unlike existing rent-seeking business models with government control – threatens the political establishment.

The growing use of tech solutions also leads to increased transparency and efficiency of service delivery, which in turn leads to increased demand for government accountability and pressure to adopt more liberal policies. Until there is a shift towards catalysing entrepreneurial leadership, there is a stronger incentive for political elites to leverage their powers to co-opt successful technology businesses, or otherwise try to control them for political gain, than let them flourish. This shift in mindset will be critical to unlocking the full potential of Africa’s young innovators.

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Sophos X-Ops unveils five-year investigation tracking China-based groups targeting perimeter devices

Wenhe Zhu
Dec 29, 2020; 0:RA120.002353v1-mcp.RA120.002353
Research

Toma Keser
Dec 29, 2020; 0:RA120.002433v1-mcp.RA120.002433
Research

Xiao-Ting Wen
Dec 17, 2020; 0:RA120.002119v1-mcp.RA120.002119
Research

Alison M. Kurimchak
Dec 1, 2020; 19:2068-2089
Research

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
Research

Annika Nelde
Dec 7, 2020; 0:R120.002309v1-mcp.R120.002309
Review

Tirsa L. E. van Westering
Dec 1, 2020; 19:2047-2067
Research

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

Autophagy plays critical roles in the maintenance of endothelial cells in response to cellular stress caused by blood flow. There is growing evidence that both cell adhesion and cell detachment can modulate autophagy, but the mechanisms responsible for this regulation remain unclear. Immunoglobulin and proline-rich receptor-1 (IGPR-1) is a cell adhesion molecule that regulates angiogenesis and endothelial barrier function. In this study, using various biochemical and cellular assays, we demonstrate that IGPR-1 is activated by autophagy-inducing stimuli, such as amino acid starvation, nutrient deprivation, rapamycin, and lipopolysaccharide. Manipulating the IκB kinase β activity coupled with in vivo and in vitro kinase assays demonstrated that IκB kinase β is a key serine/threonine kinase activated by autophagy stimuli and that it catalyzes phosphorylation of IGPR-1 at Ser220. The subsequent activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase, which leads to phosphorylation of the major pro-autophagy proteins ULK1 and Beclin-1 (BECN1), increased LC3-II levels, and accumulation of LC3 punctum. Thus, our data demonstrate that IGPR-1 is activated by autophagy-inducing stimuli and in response regulates autophagy, connecting cell adhesion to autophagy. These findings may have important significance for autophagy-driven pathologies such cardiovascular diseases and cancer and suggest that IGPR-1 may serve as a promising therapeutic target.

Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment.

Elevated levels of fasting insulin release and insufficient glucose-stimulated insulin secretion (GSIS) are hallmarks of diabetes. Studies have established cross-talk between integrin signaling and insulin activity, but more details of how integrin-dependent signaling impacts the pathophysiology of diabetes are needed. Here, we dissected integrin-dependent signaling pathways involved in the regulation of insulin secretion in β-cells and studied their link to the still debated autocrine regulation of insulin secretion by insulin/insulin-like growth factor (IGF) 2–AKT signaling. We observed for the first time a cooperation between different AKT isoforms and focal adhesion kinase (FAK)–dependent adhesion signaling, which either controlled GSIS or prevented insulin secretion under fasting conditions. Indeed, β-cells form integrin-containing adhesions, which provide anchorage to the pancreatic extracellular matrix and are the origin of intracellular signaling via FAK and paxillin. Under low-glucose conditions, β-cells adopt a starved adhesion phenotype consisting of actin stress fibers and large peripheral focal adhesion. In contrast, glucose stimulation induces cell spreading, actin remodeling, and point-like adhesions that contain phospho-FAK and phosphopaxillin, located in small protrusions. Rat primary β-cells and mouse insulinomas showed an adhesion remodeling during GSIS resulting from autocrine insulin/IGF2 and AKT1 signaling. However, under starving conditions, the maintenance of stress fibers and the large adhesion phenotype required autocrine IGF2-IGF1 receptor signaling mediated by AKT2 and elevated FAK-kinase activity and ROCK-RhoA levels but low levels of paxillin phosphorylation. This starved adhesion phenotype prevented excessive insulin granule release to maintain low insulin secretion during fasting. Thus, deregulation of the IGF2 and adhesion-mediated signaling may explain dysfunctions observed in diabetes.

Neutrophils are primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils prevent the spread of pathogens is NETosis, the extrusion of cellular DNA resulting in neutrophil extracellular traps (NETs). The protease neutrophil elastase (NE) has been implicated in the formation of NETs through proteolysis of nuclear proteins leading to chromatin decondensation. In addition to NE, neutrophils contain three other serine proteases that could compensate if the activity of NE was neutralized. However, whether they do play such a role is unknown. Thus, we deployed recently described specific inhibitors against all four of the neutrophil serine proteases (NSPs). Using specific antibodies to the NSPs along with our labeled inhibitors, we show that catalytic activity of these enzymes is not required for the formation of NETs. Moreover, the NSPs that decorate NETs are in an inactive conformation and thus cannot participate in further catalytic events. These results indicate that NSPs play no role in either NETosis or arming NETs with proteolytic activity.

Genetic mutations related to ALS, a progressive neurological disease, have been discovered in the gene encoding σ-1 receptor (σ1R). We previously reported that σ1RE102Q elicits toxicity in cells. The σ1R forms oligomeric states that are regulated by ligands. Nevertheless, little is known about the effect of ALS-related mutations on oligomer formation. Here, we transfected NSC-34 cells, a motor neuronal cell line, and HEK293T cells with σ1R-mCherry (mCh), σ1RE102Q-mCh, or nontagged forms to investigate detergent solubility and subcellular distribution using immunocytochemistry and fluorescence recovery after photobleaching. The oligomeric state was determined using crosslinking procedure. σ1Rs were soluble to detergents, whereas the mutants accumulated in the insoluble fraction. Within the soluble fraction, peak distribution of mutants appeared in higher sucrose density fractions. Mutants formed intracellular aggregates that were co-stained with p62, ubiquitin, and phosphorylated pancreatic eukaryotic translation initiation factor-2-α kinase in NSC-34 cells but not in HEK293T cells. The aggregates had significantly lower recovery in fluorescence recovery after photobleaching. Acute treatment with σ1R agonist SA4503 failed to improve recovery, whereas prolonged treatment for 48 h significantly decreased σ1RE102Q-mCh insolubility and inhibited apoptosis. Whereas σ1R-mCh formed monomers and dimers, σ1RE102Q-mCh also formed trimers and tetramers. SA4503 reduced accumulation of the four types in the insoluble fraction and increased monomers in the soluble fraction. The σ1RE102Q insolubility was diminished by σ1R-mCh co-expression. These results suggest that the agonist and WT σ1R modify the detergent insolubility, toxicity, and oligomeric state of σ1RE102Q, which may lead to promising new treatments for σ1R-related ALS.

Acute lung injury (ALI), is a rapidly progressing heterogenous pulmonary disorder that possesses a high risk of mortality. Accumulating evidence has implicated the activation of the p65 subunit of NF-κB [NF-κB(p65)] activation in the pathological process of ALI. microRNAs (miRNAs), a group of small RNA molecules, have emerged as major governors due to their post-transcriptional regulation of gene expression in a wide array of pathological processes, including ALI. The dysregulation of miRNAs and NF-κB activation has been implicated in human diseases. In the current study, we set out to decipher the convergence of miR-99b and p65 NF-κB activation in ALI pathology. We measured the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) in bronchoalveolar lavage fluid using ELISA. MH-S cells were cultured and their viability were detected with cell counting kit 8 (CCK8) assays. The results showed that miR-99b was up-regulated, while PRDM1 was down-regulated in a lipopolysaccharide (LPS)-induced murine model of ALI. Mechanistic investigations showed that NF-κB(p65) was enriched at the miR-99b promoter region, and further promoted its transcriptional activity. Furthermore, miR-99b targeted PRDM1 by binding to its 3'UTR, causing its down-regulation. This in-creased lung injury, as evidenced by increased wet/dry ratio of mouse lung, myeloperoxidase activity and pro-inflammatory cytokine secretion, and enhanced infiltration of inflammatory cells in lung tissues. Together, our findings indicate that NF-κB(p65) promotion of miR-99b can aggravate ALI in mice by down-regulating the expression of PRDM1.

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone–rod dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It required higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer—6-fold higher than WT and 2-fold higher than the Ser838-harboring homodimer. The heterodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB.

NSun2 is an RNA methyltransferase introducing 5-methylcytosine into tRNAs, mRNAs, and noncoding RNAs, thereby influencing the levels or function of these RNAs. Autotaxin (ATX) is a secreted glycoprotein and is recognized as a key factor in converting lysophosphatidylcholine into lysophosphatidic acid (LPA). The ATX-LPA axis exerts multiple biological effects in cell survival, migration, proliferation, and differentiation. Here, we show that NSun2 is involved in the regulation of cell migration through methylating ATX mRNA. In the human glioma cell line U87, knockdown of NSun2 decreased ATX protein levels, whereas overexpression of NSun2 elevated ATX protein levels. However, neither overexpression nor knockdown of NSun2 altered ATX mRNA levels. Further studies revealed that NSun2 methylated the 3'-UTR of ATX mRNA at cytosine 2756 in vitro and in vivo. Methylation by NSun2 enhanced ATX mRNA translation. In addition, NSun2-mediated 5-methylcytosine methylation promoted the export of ATX mRNA from nucleus to cytoplasm in an ALYREF-dependent manner. Knockdown of NSun2 suppressed the migration of U87 cells, which was rescued by the addition of LPA. In summary, we identify NSun2-mediated methylation of ATX mRNA as a novel mechanism in the regulation of ATX.

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Alice Santonastaso
Dec 1, 2020; 61:1687-1696
Research Articles

Elisa Vidal
Dec 1, 2020; 61:1733-1746
Research Articles

Marco De Giorgi
Dec 1, 2020; 61:1675-1686
Research Articles

Nicholas D. LeBlond
Dec 1, 2020; 61:1697-1706
Research Articles

Ryunosuke Ohkawa
Dec 1, 2020; 61:1577-1588
Research Articles

Natalie Bruiners
Dec 1, 2020; 61:1617-1628
Research Articles

Aloïs Dusuel
Dec 9, 2020; 0:jlr.RA120000704v1-jlr.RA120000704
Research Articles

Anja Jaeschke
Dec 9, 2020; 0:jlr.RA120001141v1-jlr.RA120001141
Research Articles

Abudukadier Abulizi
Dec 1, 2020; 61:1565-1576
Research Articles

Ying Zou
Dec 1, 2020; 61:1589-1604
Research Articles

Babunageswararao Kanuri
Nov 17, 2020; 0:jlr.RA120001101v1-jlr.RA120001101
Research Articles