Explore the vast range of titles available.

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1 . They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci. Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A , have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1 , which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10 −14 ) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci ( P < 5 × 10 −8 ). We identified association signals at 13q12 ( POMP ), 11q23.3 ( TMEM136 ), 6p21 ( AGPAT1 ), 3p24 ( RBMS3 ) and 5q23 (near SEMA6A ). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.

p62/SQSTM1 is known to act as a key mediator in the selective autophagy of protein aggregates, or aggrephagy, by steering ubiquitinated protein aggregates towards the autophagy pathway. Here, we use a yeast two-hybrid screen to identify the prefoldin-like chaperone UXT as an interacting protein of p62. We show that UXT can bind to protein aggregates as well as the LB domain of p62, and, possibly by forming an oligomer, increase p62 clustering for its efficient targeting to protein aggregates, thereby promoting the formation of the p62 body and clearance of its cargo via autophagy. We also find that ectopic expression of human UXT delays SOD1(A4V)-induced degeneration of motor neurons in a Xenopus model system, and that specific disruption of the interaction between UXT and p62 suppresses UXT-mediated protection. Together, these results indicate that UXT functions as an autophagy adaptor of p62-dependent aggrephagy. Furthermore, our study illustrates a cooperative relationship between molecular chaperones and the aggrephagy machinery that efficiently removes misfolded protein aggregates. p62/SQSTM1 acts as a key mediator in the selective autophagy of protein aggregates, or aggrephagy. Here the authors identify the prefoldin-like chaperone UXT as an autophagy adaptor of p62 dependent aggrephagy and show that ectopic UXT expression delays motor neuron degeneration in a Xenopus model.

Molecular chaperones promote the folding and macromolecular assembly of a diverse set of 'client' proteins. How ubiquitous chaperone machineries direct their activities towards specific sets of substrates is unclear. Through the use of mouse genetics, imaging and quantitative proteomics we uncover that ZMYND10 is a novel co-chaperone that confers specificity for the FKBP8-HSP90 chaperone complex towards axonemal dynein clients required for cilia motility. Loss of ZMYND10 perturbs the chaperoning of axonemal dynein heavy chains, triggering broader degradation of dynein motor subunits. We show that pharmacological inhibition of FKBP8 phenocopies dynein motor instability associated with the loss of ZMYND10 in airway cells and that human disease-causing variants of ZMYND10 disrupt its ability to act as an FKBP8-HSP90 co-chaperone. Our study indicates that primary ciliary dyskinesia (PCD), caused by mutations in dynein assembly factors disrupting cytoplasmic pre-assembly of axonemal dynein motors, should be considered a cell-type specific protein-misfolding disease.

The use of zinc supplement may have a negative effect on copper status. The objective of this study was to evaluate the effect of zinc and vitamin E supplementation on copper and zinc biomarkers in patients undergoing coronary artery bypass graft (CABG) surgery. The study was an add-on project to a previously published randomized controlled trial (NCT05402826) on patients undergoing CABG surgery. Patients in the zinc-vitamin E group ( n = 40) received oral zinc (120 mg) and vitamin E (1200 international units) 1 day before surgery, followed by 30 mg of zinc and 200 units of vitamin E per day until 21 days after surgery, while those in the control group ( n = 38) received placebo. Plasma levels of copper, ceruloplasmin, superoxide dismutase (SOD) activity, as well as leukocyte gene expression of metallothionein 2A (MT2A) and antioxidant protein 1 (ATOX1), were determined 3 and 21 days after surgery. The plasma copper level in the zinc-vitamin E group was significantly lower than the placebo group on the 3rd postoperative day, but no significant between-group differences were observed on day 21. Plasma ceruloplasmin concentration and SOD activity were not different. Relative mRNA expression of leukocyte MT2A was increased at both times (days 3 and 21 in the zinc-vitamin E group compared to placebo, but ATOX1 expression was not affected. Although the plasma copper level was transiently decreased early after surgery in the zinc-vitamin E group, considering the lack of change in other copper biomarkers, it seems that the use of zinc supplements at the dose used in the present study does not have a significant negative effect on the role of intracellular copper.

Protein phase separation drives the assembly of membraneless organelles, but little is known about how these membraneless organelles are maintained in a metastable liquid- or gel-like phase rather than proceeding to solid aggregation. Here, we find that human small heat-shock protein 27 (Hsp27), a canonical chaperone that localizes to stress granules (SGs), prevents FUS from undergoing liquid−liquid phase separation (LLPS) via weak interactions with the FUS low complexity (LC) domain. Remarkably, stress-induced phosphorylation of Hsp27 alters its activity, leading Hsp27 to partition with FUS LC to preserve the liquid phase against amyloid fibril formation. NMR spectroscopy demonstrates that Hsp27 uses distinct structural mechanisms for both functions. Our work reveals a fine-tuned regulation of Hsp27 for chaperoning FUS into either a polydispersed state or a LLPS state and suggests an essential role for Hsp27 in stabilizing the dynamic phase of stress granules.The chaperone Hsp27 prevents FUS from undergoing liquid–liquid phase separation until stress-induced phosphorylation causes Hsp27 to partition with FUS to preserve the liquid phase against amyloid fibril formation.

Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.Misfolded proteins have a high propensity to form potentially toxic aggregates. Cells employ a complex network of processes, involving chaperones and proteolytic machineries that ensure proper protein folding and remodel or degrade misfolded species and aggregates. This proteostasis network declines with age, which can be linked to human degenerative diseases.

Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.

Summary Crop yield has been greatly enhanced during the last century. However, most elite cultivars are adapted to temperate climates and are not well suited to more stressful conditions. In the context of climate change, stress resistance is a major concern. To overcome these difficulties, scientists may help breeders by providing genetic markers associated with stress resistance. However, multistress resistance cannot be obtained from the simple addition of single stress resistance traits. In the field, stresses are unpredictable and several may occur at once. Consequently, the use of single stress resistance traits is often inadequate. Although it has been historically linked with the heat stress response, the heat‐shock protein (HSP)/chaperone network is a major component of multiple stress responses. Among the HSP/chaperone ‘client proteins’, many are primary metabolism enzymes and signal transduction components with essential roles for the proper functioning of a cell. HSPs/chaperones are controlled by the action of diverse heat‐shock factors, which are recruited under stress conditions. In this review, we give an overview of the regulation of the HSP/chaperone network with a focus on Arabidopsis thaliana. We illustrate the role of HSPs/chaperones in regulating diverse signalling pathways and discuss several basic principles that should be considered for engineering multiple stress resistance in crops through the HSP/chaperone network.

Key Points Heat shock protein 90 (HSP90) is a molecular chaperone that is conserved from bacteria to humans and facilitates the maturation of substrates (or clients) that are involved in many different cellular pathways. HSP90 clients include, among others, kinases, transcription factors, steroid hormone receptors and E3 ubiquitin ligases. The highly dynamic conformational changes in the HSP90 dimer are regulated by a set of co-chaperones that bind to HSP90, often in different phases of its ATPase cycle. Co-chaperones modulate the rate of ATP hydrolysis by HSP90, stabilize certain conformational states or are involved in client recruitment. Some co-chaperones introduce asymmetry in the symmetric HSP90 dimer. HSP90 binds to clients in different conformations. Novel insights into client maturation have revealed that clients form contacts mainly with the middle domain of HSP90, but also make contacts with the amino-terminal and carboxy-terminal domains. HSP90 clients are functionally and structurally diverse. Within this broad range of clients, intrinsic instability and low folding cooperativity seem to dictate the requirement for the chaperone activity of HSP90. The pleiotropic effects of HSP90 on diverse client proteins means that HSP90 is implicated in many diseases, most prominently cancer, neurodegenerative diseases and infectious diseases that are caused by viruses and protozoa. A number of HSP90 inhibitors have been identified that target the ATP-binding site or the carboxy-terminal domain. A number of these are currently being evaluated in clinical trials. The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis. Recent progress has shed light on the interactions of HSP90 with its clients and co-chaperones, and on their functional implications. This opens up new avenues for the development of drugs that target HSP90, which could be valuable for the treatment of cancers and protein-misfolding diseases. The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.