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Selective macroautophagy is an important protective mechanism against diverse cellular stresses. In contrast to the well-characterized starvation-induced autophagy, the regulation of selective autophagy is largely unknown. Here, we demonstrate that Huntingtin, the Huntington disease gene product, functions as a scaffold protein for selective macroautophagy but it is dispensable for non-selective macroautophagy. In Drosophila , Huntingtin genetically interacts with autophagy pathway components. In mammalian cells, Huntingtin physically interacts with the autophagy cargo receptor p62 to facilitate its association with the integral autophagosome component LC3 and with Lys-63-linked ubiquitin-modified substrates. Maximal activation of selective autophagy during stress is attained by the ability of Huntingtin to bind ULK1, a kinase that initiates autophagy, which releases ULK1 from negative regulation by mTOR. Our data uncover an important physiological function of Huntingtin and provide a missing link in the activation of selective macroautophagy in metazoans. Zhang, Cuervo and colleagues find that Huntingtin (Htt), which is commonly mutated in Huntington disease, regulates selective autophagy. Htt enhances interactions between p62, LC3 and ubiquitylated cargo and derepresses ULK1 kinase activity.

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression. The tau protein has been implicated in neurodegenerative disorders and can propagate from cell to cell. Here, the authors show that tau acetylation reduces its degradation by chaperone-mediated autophagy, causing re-routing to other autophagic pathways and increasing extracellular tau release.

Nutrient deprivation is a stimulus shared by both autophagy and the formation of primary cilia. The recently discovered role of primary cilia in nutrient sensing and signalling motivated us to explore the possible functional interactions between this signalling hub and autophagy. Here we show that part of the molecular machinery involved in ciliogenesis also participates in the early steps of the autophagic process. Signalling from the cilia, such as that from the Hedgehog pathway, induces autophagy by acting directly on essential autophagy-related proteins strategically located in the base of the cilium by ciliary trafficking proteins. Whereas abrogation of ciliogenesis partially inhibits autophagy, blockage of autophagy enhances primary cilia growth and cilia-associated signalling during normal nutritional conditions. We propose that basal autophagy regulates ciliary growth through the degradation of proteins required for intraflagellar transport. Compromised ability to activate the autophagic response may underlie some common ciliopathies. The primary cilium is a microtubule-based organelle that functions in sensory and signal transduction; here the authors show that the primary cilium is required for activation of starvation-induced autophagy and that basal autophagy negatively regulates ciliogenesis. Autophagy's links with ciliogenesis The primary cilium is a non-motile signalling organelle found in a specific region of the plasma membrane where it functions in both signal transduction and sensing environmental cues such as nutrient levels. Two complementary papers published in this week's issue of Nature describe a novel link between ciliogenesis and autophagy. Zaiming Tang et al . demonstrate that autophagic degradation of a negative regulator of cilia formation, oral-facial-digital syndrome 1 (OFD1), at centriolar satellites promotes primary cilium biogenesis. Olatz Pampliega et al . uncover a reciprocal relationship between ciliogenesis and autophagy and show that the primary cilium is required for activation of starvation-induced autophagy, and that autophagy negatively regulates ciliogenesis. Cross-talk between the primary cilium and the autophagy pathway may further lead to our understanding of human ciliary diseases.

Summary Chaperone-mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver-specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging. Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging.

Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration. Gomez-Sintes et al. have developed small molecules that selectively activate chaperone-mediated autophagy by stabilizing the interaction between retinoic acid receptor alpha and its co-repressor N-CoR1. They demonstrate the protective effect of boosting chaperone-mediated autophagy against retinal degeneration.

Objective The current global COVID-19 pandemic has disrupted supply chains and the production of essential goods and services. This includes personal protective equipment (PPE) kits, respirators, and other protective devices. Hence efforts were made to prototype and produce 3D-printed N95 respirators to fill the gap in supply. In addition, methods of sterilization were put into place for the respirators. As well as forming standard operating procedures. Methods With the use of vast open-source libraries and collaboration with engineers and doctors fighting the COVID-19 pandemic, respirator prototypes were produced with special consideration to the sizing to fit median facial sizes. Polymer plastics were mixed in various proportions to condition the respirator to be used by frontline workers in austere environments. Due to the shortage of medical-grade filter media, alternative sources were researched. Merv 13 and Merv 15 filters were selected due to their cheap costs, vast abundance, and proven filtration efficacy against particles of 0.03 microns. Studies conducted around the world have also shown its efficacy as an alternative to medical-grade air filter media. After developing standard operating procedures (SOPs) for sterilisation and respirator usage. Emergency approval was obtained and a limited number of healthcare workers were issued with this respirator (n=400). PPE kit satisfaction and self-efficacy scores were calculated from daily questionnaires during donning and doffing Results Qualitative fit-tests in all 400 healthcare workers matched those of a conventional N95 respirator. Almost all of the respondents in the PPE kit satisfaction responded positively. The self-efficacy score calculated from the general self-efficiency scale had an overall positive value, with the average score being 4.29. This demonstrated that the self-efficacy score was above average and indicated a high motivation to overcome obstacles and spend more time solving problems. The average self-efficacy score is defined between 2.5 - 3.5, and a low self-efficacy score is defined as a score below 2.5. Lastly, a regression analysis was done to test the correlation between PPE kit satisfaction and self-efficiency this demonstrated a positive correlation between PPE kit satisfaction using the 3D-printed respirator and self-efficacy (Slope: 0.416, Intercept: -1.066, R-value: 0.872, P-value: <0.01) Conclusions With supply chain disruptions and reduced or nonexistent supplies of essential medical goods. The need of a reusable, sterilisable, and efficient respirator has never been more evident. The materials used have made it sustain heavy use in austere environments. Studies have reported higher than average burnout rates in COVID-19-based healthcare workers. Studies have also shown that the rates of burnout are high in healthcare professionals without access to proper PPE kits in developing nations. This respirator was rated highly in PPE kit satisfaction and the self-efficacy score. Studies have demonstrated a correlation between high self-efficacy scores and low burnout rates in health care workers. There is also documented evidence of a positive correlation between high self-efficacy scores and general health. As the pandemic continues to evolve, so will the efforts to combat it, such as 3D printing. Interdisciplinary collaboration continues to drive our efforts to combat the pandemic and hopefully resolve it in the future.

Although vaccination has been heralded as one of the 10 greatest public health achievements, how parents differ in their views about vaccination is not well understood. A deeper understanding of these attitudes and beliefs may improve the effectiveness of vaccine communications. In this mailed survey of U.S. parents in January 2001 (return response rate 49%), parental confidence in vaccination was very high, although there was significant variation among parents. Using multivariate analyses to group and profile parents, 90% of parents ( n = 1820) were classified into one of four distinct parent groups: (1) “Vaccine Believer” parents who were convinced of the benefit of vaccination; (2) “Cautious” parents noteworthy for a high emotional investment in their child; (3) “Relaxed” parents characterized by a less involved parenting style and some skepticism about vaccines; and (4) “Unconvinced” parents distinguished by their distrust of vaccinations and vaccination policy. These findings suggest that messages that are customized to parents’ attitudes and beliefs may improve their understanding and acceptance of vaccination.

Lipid modifications are essential in cellular sorting and trafficking inside cells. The role of phosphoinositides in trafficking between Golgi and endocytic/lysosomal compartments has been extensively explored and the kinases responsible for these lipid changes have been identified. In contrast, the mechanisms that mediate exit and recycling from lysosomes (Lys), considered for a long time as terminal compartments, are less understood. In this work, we identify a dynamic association of the lipid kinase PI4KIIIβ with Lys and unveil its regulatory function in lysosomal export and retrieval. We have found that absence of PI4KIIIβ leads to abnormal formation of tubular structures from the lysosomal surface and loss of lysosomal constituents through these tubules. We demonstrate that the kinase activity of PI4KIIIβ is necessary to prevent this unwanted lysosomal efflux under normal conditions, and to facilitate proper sorting when recycling of lysosomal material is needed, such as in the physiological context of lysosomal reformation after prolonged starvation. The recycling of proteins from lysosomes remains ill understood. The lipid kinase PI4KIIIβ prevents continuous lysosomal efflux and assures efficient recycling of lysosomal material. Loss of PI4KIIIβ activity leads to formation of abnormal tubular structures on lysosomes.

The plasma membrane contributes to the formation of autophagosomes, the double-membrane vesicles that sequester cytosolic cargo and deliver it to lysosomes for degradation during autophagy. In this study, we have identified a regulatory role for connexins (Cx), the main components of plasma membrane gap junctions, in autophagosome formation. We have found that plasma-membrane-localized Cx proteins constitutively downregulate autophagy through a direct interaction with several autophagy-related proteins involved in the initial steps of autophagosome formation, such as Atg16 and components of the PI(3)K autophagy initiation complex (Vps34, Beclin-1 and Vps15). On nutrient starvation, this inhibitory effect is released by the arrival of Atg14 to the Cx–Atg complex. This promotes the internalization of Cx–Atg along with Atg9, which is also recruited to the plasma membrane in response to starvation. Maturation of the Cx-containing pre-autophagosomes into autophagosomes leads to degradation of these endogenous inhibitors, allowing for sustained activation of autophagy. Connexins localize to the plasma membrane, where they form gap junctions between cells. Cuervo and colleagues report that connexins associate with autophagosome precursor structures in the plasma membrane and inhibit autophagosome biogenesis. Nutrient deprivation relieves this inhibition and promotes autophagic degradation of connexin proteins.

BackgroundThe Alpha variant (B.1.1.7 lineage) of SARS-CoV-2 emerged and became the dominant circulating variant in the UK in late 2020. Current literature is unclear on whether the Alpha variant is associated with increased severity. We linked clinical data with viral genome sequence data to compare admitted cases between SARS-CoV-2 waves in London and to investigate the association between the Alpha variant and the severity of disease.MethodsClinical, demographic, laboratory and viral sequence data from electronic health record systems were collected for all cases with a positive SARS-CoV-2 RNA test between 13 March 2020 and 17 February 2021 in a multisite London healthcare institution. Multivariate analysis using logistic regression assessed risk factors for severity as defined by hypoxia at admission.ResultsThere were 5810 SARS-CoV-2 RNA-positive cases of which 2341 were admitted (838 in wave 1 and 1503 in wave 2). Both waves had a temporally aligned rise in nosocomial cases (96 in wave 1 and 137 in wave 2). The Alpha variant was first identified on 15 November 2020 and increased rapidly to comprise 400/472 (85%) of sequenced isolates from admitted cases in wave 2. A multivariate analysis identified risk factors for severity on admission, such as age (OR 1.02, 95% CI 1.01 to 1.03, for every year older; p<0.001), obesity (OR 1.70, 95% CI 1.28 to 2.26; p<0.001) and infection with the Alpha variant (OR 1.68, 95% CI 1.26 to 2.24; p<0.001).ConclusionsOur analysis is the first in hospitalised cohorts to show increased severity of disease associated with the Alpha variant. The number of nosocomial cases was similar in both waves despite the introduction of many infection control interventions before wave 2.