bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒04‒10
eighteen papers selected by
Rich Giadone
Harvard University
  1. A Census of Hsp70-Mediated Proteome Solubility Changes upon Recovery from Heat Stress.
  2. CCT2 is an aggrephagy receptor for clearance of solid protein aggregates.
  3. An unexpected protein aggregate in diseased and ageing brains.
  4. A switch of chaperonin function regulates the clearance of solid protein aggregates.
  5. Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation.
  6. Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.
  7. Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice.
  8. Chaperoning solid aggregates for autophagy.
  9. Early Adversity and Accelerated Brain Aging: A Mini-Review.
  10. Multiomic profiling of the acute stress response in the mouse hippocampus.
  11. Autophagy Reprogramming Stem Cell Pluripotency and Multiple-lineage Differentiation.
  12. Cell type determination for cardiac differentiation occurs soon after seeding of human-induced pluripotent stem cells.
  13. Targeted protein degraders march towards the clinic for neurodegenerative diseases.
  14. Brain charts for the human lifespan.
  15. A role for endoplasmic reticulum dynamics in the cellular distribution of microtubules.
  16. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming.
  17. Heat shock proteins and the calcineurin-crz1 signaling regulate stress responses in fungi.
  18. Diverse Molecular Mechanisms Underlying Pathogenic Protein Mutations: Beyond the Loss-of-Function Paradigm.
  1. J Proteome Res. 2022 Apr 07.
    A Census of Hsp70-Mediated Proteome Solubility Changes upon Recovery from Heat Stress.
    Xiaojing Sui, Dezerae Cox, Shuai Nie, Gavin E Reid, Danny M Hatters.
      Eukaryotic cells respond to heat shock through several regulatory processes including upregulation of stress responsive chaperones and reversible shutdown of cellular activities through formation of protein assemblies. However, the underlying regulatory mechanisms of the recovery of these heat-induced protein assemblies remain largely elusive. Here, we measured the proteome abundance and solubility changes during recovery from heat shock in the mouse Neuro2a cell line. We found that prefoldins and translation machinery are rapidly down-regulated as the first step in the heat shock response. Analysis of proteome solubility reveals that a rapid mobilization of protein quality control machineries, along with changes in cellular energy metabolism, translational activity, and actin cytoskeleton are fundamental to the early stress responses. In contrast, longer term adaptation to stress involves renewal of core cellular components. Inhibition of the Hsp70 family, pivotal for the heat shock response, selectively and negatively affects the ribosomal machinery and delays the solubility recovery of many nuclear proteins. ProteomeXchange: PXD030069.
    Keywords:  chaperone; disaggregation; heat shock; heat shock protein 70; protein solubility; quantitative proteomics; recovery
    DOI:  https://doi.org/10.1021/acs.jproteome.1c00920
  2. Cell. 2022 Mar 27. pii: S0092-8674(22)00265-3. [Epub ahead of print]
    CCT2 is an aggrephagy receptor for clearance of solid protein aggregates.
    Xinyu Ma, Caijing Lu, Yuting Chen, Shulin Li, Ningjia Ma, Xuan Tao, Ying Li, Jing Wang, Min Zhou, Yong-Bin Yan, Pilong Li, Kartoosh Heydari, Haiteng Deng, Min Zhang, Cong Yi, Liang Ge.
      Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been elusive. Here, we identify the chaperonin subunit CCT2 as an autophagy receptor regulating the clearance of aggregation-prone proteins in the cell and the mouse brain. CCT2 associates with aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independently of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or chaperone-mediated autophagy. Unlike P62, NBR1, and TAX1BP1, which facilitate the clearance of protein condensates with liquidity, CCT2 specifically promotes the autophagic degradation of protein aggregates with little liquidity (solid aggregates). Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR to ATG8s interaction and, therefore, enables the autophagic function.
    Keywords:  CCT2; FUS; GABARAP; Huntington’s disease; LC3; NBR1; P62; SOD1; TAX1BP1; TRiC; aggrephagy; autophagy; chaperone; chaperonin; huntingtin; neurodegeneration; phase separation; protein aggregates; protein aggregation; tau
    DOI:  https://doi.org/10.1016/j.cell.2022.03.005
  3. Nature. 2022 Apr 04.
    An unexpected protein aggregate in diseased and ageing brains.
    Hideyuki Takahashi, Stephen M Strittmatter.
      
    Keywords:  Neurodegeneration; Structural biology
    DOI:  https://doi.org/10.1038/d41586-022-00873-2
  4. Autophagy. 2022 Apr 05. 1-3
    A switch of chaperonin function regulates the clearance of solid protein aggregates.
    Xinyu Ma, Min Zhang, Liang Ge.
      Protein aggregation is related to many human diseases. Selective macroautophagy/autophagy is the major way to clear protein aggregates in eukaryotic cells. While multiple types of autophagy receptors have been reported to mediate autophagic clearance of protein condensates with liquidity, it has been unclear if and how solid aggregates could be degraded by autophagy. Our recent work identifies the chaperonin subunit CCT2 as a new type of aggrephagy receptor specifically facilitating the autophagic clearance of solid protein aggregates, and indicates that multiple aggrephagy pathways act in parallel to remove different types of protein aggregates. In addition, this work reveals a functional switch of the chaperonin system by showing that CCT2 acts both as a chaperonin component and an autophagy-receptor via complex and monomer formation.
    Keywords:  Aggrephagy; CCT2; TRiC; autophagosome; autophagy; chaperone; chaperonin; phase separation; protein aggregation
    DOI:  https://doi.org/10.1080/15548627.2022.2052581
  5. Nat Commun. 2022 Apr 05. 13(1): 1821
    Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation.
    Kristine F R Pobre-Piza, Melissa J Mann, Ashley R Flory, Linda M Hendershot.
      BiP co-chaperones ERdj4, ERdj5, and GRP170 associate in cells with peptides predicted to be aggregation prone. Here, extending these findings to a full-length protein, we examine two Interstitial Lung Disease-associated mutants (ILD) of surfactant protein C (SP-C). The TANGO algorithm, which identifies sequences prone to formation of β strand aggregates, found three such regions in SP-C: the N-terminal transmembrane (TM) domain and two sites in the intermolecular chaperone BRICHOS domain. We show the ILD mutants disrupt di-sulfide bond formation in the BRICHOS domain and expose the aggregation-prone peptides leading to binding of ERdj4, ERdj5, and GRP170. The destabilized mutant BRICHOS domain fails to properly insert its TM region in the ER membrane, exposing part of the N-terminal TM domain site. Our studies with ILD-associated mutant proteins provide insights into the specificity of ERdj4, ERdj5, and GRP170, identify context-dependent differences in their binding, and reveal molecular consequences of disease-associated mutants on folding.
    DOI:  https://doi.org/10.1038/s41467-022-29478-z
  6. Sci Adv. 2022 Apr 08. 8(14): eabm2094
    Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state.
    Joseph E Chambers, Nikita Zubkov, Markéta Kubánková, Jonathon Nixon-Abell, Ioanna Mela, Susana Abreu, Max Schwiening, Giulia Lavarda, Ismael López-Duarte, Jennifer A Dickens, Tomás Torres, Clemens F Kaminski, Liam J Holt, Edward Avezov, James A Huntington, Peter St George-Hyslop, Marina K Kuimova, Stefan J Marciniak.
      Misfolding of secretory proteins in the endoplasmic reticulum (ER) features in many human diseases. In α1-antitrypsin deficiency, the pathogenic Z variant aberrantly assembles into polymers in the hepatocyte ER, leading to cirrhosis. We show that α1-antitrypsin polymers undergo a liquid:solid phase transition, forming a protein matrix that retards mobility of ER proteins by size-dependent molecular filtration. The Z-α1-antitrypsin phase transition is promoted during ER stress by an ATF6-mediated unfolded protein response. Furthermore, the ER chaperone calreticulin promotes Z-α1-antitrypsin solidification and increases protein matrix stiffness. Single-particle tracking reveals that solidification initiates in cells with normal ER morphology, previously assumed to represent a healthy pool. We show that Z-α1-antitrypsin-induced hypersensitivity to ER stress can be explained by immobilization of ER chaperones within the polymer matrix. This previously unidentified mechanism of ER dysfunction provides a template for understanding a diverse group of related proteinopathies and identifies ER chaperones as potential therapeutic targets.
    DOI:  https://doi.org/10.1126/sciadv.abm2094
  7. Front Aging Neurosci. 2022 ;14 838803
    Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice.
    Yuan Wang, Yi-Kai Jin, Tie-Cheng Guo, Zhen-Rong Li, Bing-Yan Feng, Jin-Hong Han, Martin Vreugdenhil, Cheng-Biao Lu.
      Aim: Neural network oscillation at gamma frequency band (γ oscillation, 30-80 Hz) is synchronized synaptic potentials important for higher brain processes and altered in normal aging. Recent studies indicate that activation of dopamine 4 receptor (DR4) enhanced hippocampal γ oscillation of young mice and fully recovered the impaired hippocampal synaptic plasticity of aged mice, we determined whether this receptor is involved in aging-related modulation of hippocampal γ oscillation.Methods: We recorded γ oscillations in the hippocampal CA3 region from young and aged C57bl6 mice and investigated the effects of dopamine and the selective dopamine receptor (DR) agonists on γ oscillation.
    Results: We first found that γ oscillation power (γ power) was reduced in aged mice compared to young mice, which was restored by exogenous application of dopamine (DA). Second, the selective agonists for different D1- and D2-type dopamine receptors increased γ power in young mice but had little or small effect in aged mice. Third, the D4 receptor (D4R) agonist PD168077 caused a large increase of γ power in aged mice but a small increase in young mice, and its effect is blocked by the highly specific D4R antagonist L-745,870 or largely reduced by a NMDAR antagonist. Fourth, D3R agonist had no effect on γ power of either young or aged mice.
    Conclusion: This study reveals DR subtype-mediated hippocampal γ oscillations is aging-related and DR4 activation restores the impaired γ oscillations in aged brain, and suggests that D4R is the potential target for the improvement of cognitive deficits related to the aging and aging-related diseases.
    Keywords:  ageing; dopamine; dopamine receptor; hippocampus; γ oscillation
    DOI:  https://doi.org/10.3389/fnagi.2022.838803
  8. Nat Rev Mol Cell Biol. 2022 Apr 05.
    Chaperoning solid aggregates for autophagy.
    Paulina Strzyz.
      
    DOI:  https://doi.org/10.1038/s41580-022-00482-x
  9. Front Mol Neurosci. 2022 ;15 822917
    Early Adversity and Accelerated Brain Aging: A Mini-Review.
    Pratik R Chaudhari, Aastha Singla, Vidita A Vaidya.
      Early adversity is an important risk factor that influences brain aging. Diverse animal models of early adversity, including gestational stress and postnatal paradigms disrupting dam-pup interactions evoke not only persistent neuroendocrine dysfunction and anxio-depressive behaviors, but also perturb the trajectory of healthy brain aging. The process of brain aging is thought to involve hallmark features such as mitochondrial dysfunction and oxidative stress, evoking impairments in neuronal bioenergetics. Furthermore, brain aging is associated with disrupted proteostasis, progressively defective epigenetic and DNA repair mechanisms, the build-up of neuroinflammatory states, thus cumulatively driving cellular senescence, neuronal and cognitive decline. Early adversity is hypothesized to evoke an "allostatic load" via an influence on several of the key physiological processes that define the trajectory of healthy brain aging. In this review we discuss the evidence that animal models of early adversity impinge on fundamental mechanisms of brain aging, setting up a substratum that can accelerate and compromise the time-line and nature of brain aging, and increase risk for aging-associated neuropathologies.
    Keywords:  cognition; early stress; hippocampus; maternal separation; mitochondria; neuroinflammation; neuronal survival; proteostasis
    DOI:  https://doi.org/10.3389/fnmol.2022.822917
  10. Nat Commun. 2022 Apr 05. 13(1): 1824
    Multiomic profiling of the acute stress response in the mouse hippocampus.
    Lukas M von Ziegler, Amalia Floriou-Servou, Rebecca Waag, Rebecca R Das Gupta, Oliver Sturman, Katharina Gapp, Christina A Maat, Tobias Kockmann, Han-Yu Lin, Sian N Duss, Mattia Privitera, Laura Hinte, Ferdinand von Meyenn, Hanns U Zeilhofer, Pierre-Luc Germain, Johannes Bohacek.
      The acute stress response mobilizes energy to meet situational demands and re-establish homeostasis. However, the underlying molecular cascades are unclear. Here, we use a brief swim exposure to trigger an acute stress response in mice, which transiently increases anxiety, without leading to lasting maladaptive changes. Using multiomic profiling, such as proteomics, phospho-proteomics, bulk mRNA-, single-nuclei mRNA-, small RNA-, and TRAP-sequencing, we characterize the acute stress-induced molecular events in the mouse hippocampus over time. Our results show the complexity and specificity of the response to acute stress, highlighting both the widespread changes in protein phosphorylation and gene transcription, and tightly regulated protein translation. The observed molecular events resolve efficiently within four hours after initiation of stress. We include an interactive app to explore the data, providing a molecular resource that can help us understand how acute stress impacts brain function in response to stress.
    DOI:  https://doi.org/10.1038/s41467-022-29367-5
  11. J Chin Med Assoc. 2022 Apr 05.
    Autophagy Reprogramming Stem Cell Pluripotency and Multiple-lineage Differentiation.
    Yi-Ping Yang, Wei-Yi Lai, Tzu-Wei Lin, Yi-Ying Lin, Yueh Chien, Yi-Ching Tsai, Hsiao-Yun Tai, Chia-Lin Wang, Yung-Yang Liu, Pin-I Huang, Yi-Wei Chen, Wen-Liang Lo, Chien-Ying Wang.
      The cellular process responsible for the degradation of cytosolic proteins and subcellular organelles in lysosomes was termed "autophagy" This process occurs at a basal level in most tissues as part of tissue homeostasis that redounds to the regular turnover of components inside cytoplasm. The breakthrough in the autophagy field is the identification of key players in the autophagy pathway, compounded under the name 'autophagy-related genes (ATG) encoding for autophagy effector proteins. Generally, the function of autophagy can be classified into two divisions: intracellular clearance of defective macromolecules and organelles and generation of degradation products. Therapeutic strategies using stem cell-based approach come as a promising therapy and develop rapidly recently as stem cells have high self-renewability and differentiation capability as known as mesenchymal stem cells (MSCs). They are defined as adherent fibroblast-like population with the abilities to self-renew and multi-lineage differentiate into osteogenic, adipogenic, and chondrogenic lineage cells. To date, they are the most extensively applied adult stem cells in clinical trials. The properties of MSCs such as immunomodulation, neuroprotection and tissue repair pertaining to cell differentiation processes to replace lost, or damaged cells, for aiding cell repair and revival. Autophagy has come into view as a remarkable mechanism for maintaining homeostasis as well as ensure the adequate function and survival of long-lived stem cells also plays remarkable roles in protecting stem cells against cellular stress when the stem cell regenerative capacity is harmed in the aging and degenerative. The therapeutic use of MSCs could obtain a strong improvement through the understanding of underexplored mechanisms in MSC actions and expand the spectrum of their clinical applications.
    DOI:  https://doi.org/10.1097/JCMA.0000000000000728
  12. Genome Biol. 2022 Apr 05. 23(1): 90
    Cell type determination for cardiac differentiation occurs soon after seeding of human-induced pluripotent stem cells.
    Connie L Jiang, Yogesh Goyal, Naveen Jain, Qiaohong Wang, Rachel E Truitt, Allison J Coté, Benjamin Emert, Ian A Mellis, Karun Kiani, Wenli Yang, Rajan Jain, Arjun Raj.
      BACKGROUND: Cardiac differentiation of human-induced pluripotent stem (hiPS) cells consistently produces a mixed population of cardiomyocytes and non-cardiac cell types, even when using well-characterized protocols. We sought to determine whether different cell types might result from intrinsic differences in hiPS cells prior to the onset of differentiation.RESULTS: By associating individual differentiated cells that share a common hiPS cell precursor, we tested whether expression variability is predetermined from the hiPS cell state. In a single experiment, cells that shared a progenitor were more transcriptionally similar to each other than to other cells in the differentiated population. However, when the same hiPS cells were differentiated in parallel, we did not observe high transcriptional similarity across differentiations. Additionally, we found that substantial cell death occurs during differentiation in a manner that suggested all cells were equally likely to survive or die, suggesting that there is no intrinsic selection bias for cells descended from particular hiPS cell progenitors. We thus wondered how cells grow spatially during differentiation, so we labeled cells by expression of marker genes and found that cells expressing the same marker tended to occur in patches. Our results suggest that cell type determination across multiple cell types, once initiated, is maintained in a cell-autonomous manner for multiple divisions.
    CONCLUSIONS: Altogether, our results show that while substantial heterogeneity exists in the initial hiPS cell population, it is not responsible for the variability observed in differentiated outcomes; instead, factors specifying the various cell types likely act during a window that begins shortly after the seeding of hiPS cells for differentiation.
    DOI:  https://doi.org/10.1186/s13059-022-02654-6
  13. Ageing Res Rev. 2022 Apr 01. pii: S1568-1637(22)00058-7. [Epub ahead of print] 101616
    Targeted protein degraders march towards the clinic for neurodegenerative diseases.
    Dhiraj Kumar, Md Imtaiyaz Hassan.
      Protein degraders are emerging as a potent therapeutic tool to address neurological disorders and many complex diseases. It offered several key advantages, including the doses, drug resistance, and side effects over traditional occupancy-based inhibitors. Translation of chemical degraders into a clinical therapy for neurodegenerative disorders has a well-documented knowledge and resource gap. Researchers strive to develop clinical candidates employing chemical degraders' technologies, including hydrophobic tagging, molecular glues, proteolysis targeting chimeras (PROTACs), specific and nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent protein erasers (SNIPERs), autophagy targeted chimeras, and autophagosome-tethered compounds for targeted degradation of pathological markers in neurodegenerative disease. Herein, we examined the present state of chemical-mediated targeted protein degradation in the quest for medications to treat neurodegenerative diseases. We further identified targeted degraders under clinical development for neurodegenerative diseases summarizing pertinent discoveries guiding the future of degradation therapeutics. We also addressed the necessary pharmacological interventions needed to achieve unprecedented therapeutic efficacy and its associated challenges.
    Keywords:  Protein degraders; Targeted therapy; autophagosomes; drug development, pharmaceutical research; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.arr.2022.101616
  14. Nature. 2022 Apr 06.
    Brain charts for the human lifespan.
    3R-BRAIN
      Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
    DOI:  https://doi.org/10.1038/s41586-022-04554-y
  15. Proc Natl Acad Sci U S A. 2022 Apr 12. 119(15): e2104309119
    A role for endoplasmic reticulum dynamics in the cellular distribution of microtubules.
    Maria S Tikhomirova, Avihay Kadosh, Aksel J Saukko-Paavola, Tom Shemesh, Robin W Klemm.
      SignificanceThe endoplasmic reticulum (ER) and the microtubule (MT) cytoskeleton form a coextensive, dynamic system that pervades eukaryotic cells. The shape of the ER is generated by a set of evolutionarily conserved membrane proteins that are able to control ER morphology and dynamics independently of MTs. Here we uncover that the molecular machinery that determines ER network dynamics can influence the subcellular distribution of MTs. We show that active control of local ER tubule junction density by ER tethering and fusion is important for the spatial organization of the combined ER-MT system. Our work suggests that cells might alter ER junction dynamics to drive formation of MT bundles, which are important structures, e.g., in migrating cells or in neuronal axons.
    Keywords:  cellular organization; endoplasmic reticulum; microtubule bundles; microtubules
    DOI:  https://doi.org/10.1073/pnas.2104309119
  16. Elife. 2022 Apr 08. pii: e71624. [Epub ahead of print]11
    Multi-omic rejuvenation of human cells by maturation phase transient reprogramming.
    Diljeet Gill, Aled Parry, Fátima Santos, Hanneke Okkenhaug, Christopher D Todd, Irene Hernando-Herraez, Thomas M Stubbs, Inês Milagre, Wolf Reik.
      Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming, somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first 'maturation phase transient reprogramming' (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells temporarily lose and then reacquire their fibroblast identity during MPTR, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that more extensive reprogramming does not necessarily result in greater rejuvenation but instead that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.
    Keywords:  genetics; genomics; human; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.71624
  17. Arch Microbiol. 2022 Apr 04. 204(5): 240
    Heat shock proteins and the calcineurin-crz1 signaling regulate stress responses in fungi.
    Avishek Roy, Ranjan Tamuli.
      The heat shock proteins (Hsps) act as a molecular chaperone to stabilize client proteins involved in various cell functions in fungi. Hsps are classified into different families such as HSP90, HSP70, HSP60, HSP40, and small HSPs (sHsps). Hsp90, a well-studied member of the Hsp family proteins, plays a role in growth, cell survival, and pathogenicity in fungi. Hsp70 and sHsps are involved in the development, tolerance to stress conditions, and drug resistance in fungi. Hsp60 is a mitochondrial chaperone, and Hsp40 regulates fungal ATPase machinery. In this review, we describe the cell functions, regulation, and the molecular link of the Hsps with the calcineurin-crz1 calcium signaling pathway for their role in cell survival, growth, virulence, and drug resistance in fungi and related organisms.
    Keywords:  Antifungal drug; Calcienruin-crz1; Calcium; Heat shock proteins; Stress response
    DOI:  https://doi.org/10.1007/s00203-022-02833-w
  18. Annu Rev Genomics Hum Genet. 2022 Apr 08.
    Diverse Molecular Mechanisms Underlying Pathogenic Protein Mutations: Beyond the Loss-of-Function Paradigm.
    Lisa Backwell, Joseph A Marsh.
      Most known disease-causing mutations occur in protein-coding regions of DNA. While some of these involve a loss of protein function (e.g., through premature stop codons or missense changes that destabilize protein folding), many act via alternative molecular mechanisms and have dominant-negative or gain-of-function effects. In nearly all cases, these non-loss-of-function mutations can be understood by considering interactions of the wild-type and mutant protein with other molecules, such as proteins, nucleic acids, or small ligands and substrates. Here, we review the diverse molecular mechanisms by which pathogenic mutations can have non-loss-of-function effects, including by disrupting interactions, increasing binding affinity, changing binding specificity, causing assembly-mediated dominant-negative and dominant-positive effects, creating novel interactions, and promoting aggregation and phase separation. We believe that increased awareness of these diverse molecular disease mechanisms will lead to improved diagnosis (and ultimately treatment) of human genetic disorders. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-genom-111221-103208
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