Abstract Genetic variation in human populations can result in the misfolding and aggregation of proteins, giving rise to systemic and neurodegenerative diseases that require management by proteostasis. Here, we define the role of GRP94, the endoplasmic reticulum Hsp90 chaperone paralog, in managing alpha-1-antitrypsin deficiency on a residue-by-residue basis using Gaussian process regression-based machine learning to profile the spatial covariance relationships that dictate protein folding arising from sequence variants in the population. Covariance analysis suggests a role for the ATPase activity of GRP94 in controlling the N- to C-terminal cooperative folding of alpha-1-antitrypsin responsible for the correction of liver aggregation and lung-disease phenotypes of alpha-1-antitrypsin deficiency. Gaussian process-based spatial covariance profiling provides a standard model built on covariant principles to evaluate the role of proteostasis components in guiding information flow from genome to proteome in response to genetic variation, potentially allowing us to intervene in the onset and progression of complex multi-system human diseases. 

Tracing genetic diversity captures the molecular basis of misfolding disease

Protein clearance is fundamental to proteome health. In eukaryotes, it is carried out by two highly conserved proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). Despite their pivotal role, the basal organization of the human protein clearance systems across tissues and cell types remains uncharacterized. Here, we interrogated this organization using diverse bulk and single cell omics datasets. Relative to other protein-coding genes, UPS and ALP genes were more widely expressed, encoded more housekeeping proteins, and were more essential for growth, in accordance with their fundamental roles. Yet, UPS and ALP subsystems had varied expression patterns, and each system showed a layered organization. The smaller layer included genes that were stably and widely expressed across tissues, had elevated expression levels, interacted with more proteins, and were more essential for growth, suggesting that they act as a core. The second larger layer included genes that were differentially expressed across tissues. Tissue-specific upregulation of those genes was associated with tissue-specific functions, phenotypes, and disease susceptibility, as demonstrated computationally and experimentally. Last, we compared protein clearance to other branches of the proteostasis network. Protein clearance and folding were closely coordinated across tissues and more plastic than protein synthesis. Taken together, we propose that the human proteostasis network is organized hierarchically and is tailored to varied proteome compositions. This organization could contribute to and illuminate tissue-selective phenotypes.Abbreviations: ALP: autophagy-lysosome pathway; CDA: chaperone-directed autophagy; DUBs: deubiquitinases; ESCRT: endosomal sorting complexes required for transport; KS: Kolmogorov-Smirnov; MW: Mann-Whitney; TE: tissue-enriched; TS: tissue-specific; UBL: ubiquitin-like protein; UPS: ubiquitin-proteasome system.

Human clearance systems have a layered architecture across tissues and cell types that supports varied proteome compositions

As the global demographics shifts towards an increasingly aging population, understanding the effects and molecular mechanisms underlying aging becomes more and more important within biomedical research. A hallmark of aging is the progressive deterioration of protein homeostasis (proteostasis), characterized by the accumulation of misfolded protein aggregates within the cell. The proteostasis network is essential in mitigating the harmful effects of proteotoxic aggregates by activating stress response and degradation pathways. Significant discoveries in aging research are often inherently intertwined with proteostasis, many of which were made using the invertebrate Caenorhabditis elegans. Many longevity pathways, such as the insulin-like signaling pathway, initially identified in C. elegans, are mediated through inter-tissue stress signaling from the nervous system, intestine, or gonad. These cell nonautonomous signaling pathways not only enhance lifespan and stress resilience but also limit age-related accumulation of protein aggregates that exacerbate age-associated diseases. Thus, findings from aging research were often key to providing new insights into cell nonautonomous regulation of stress responses and organismal proteostasis. In this review, we outline key discoveries made using C. elegans as a model system and highlight their contributions that led to our current understanding of inter-tissue communication in organismal proteostasis regulation. We furthermore highlight emerging concepts and discuss the translational relevance of conserved cell nonautonomous proteostasis regulation in mammals. We emphasize the importance of mammalian research to support the research done in C. elegans, with the future goal of developing potential therapeutic interventions targeting these inter-tissue proteostasis signaling pathways to combat aging. 

Signal relay in C. elegans: A tissue-perspective on coordinating organismal proteostasis and its impact on aging

Protein quality control pathways ensure a functional proteome and rely on a complex proteostasis network (PN) that is composed of molecular chaperones and proteases. Failures in the PN can lead to a broad spectrum of diseases, including neurodegenerative disorders like Alzheimer's, Parkinson's, and a range of motor neuron diseases. The EMBO workshop "Protein quality control: from molecular mechanisms to therapeutic intervention" covered all aspects of protein quality control from underlying molecular mechanisms of chaperones and proteases to stress signaling pathways and medical implications. This report summarizes the workshop and highlights selected presentations. 

Protein quality control: from molecular mechanisms to therapeutic intervention-EMBO workshop, May 21-26 2023, Srebreno, Croatia.

Autophagy activation has the potential to ameliorate neurodegenerative disease phenotypes, including protein aggregation, lipid level perturbations and axonal trafficking defects. We performed a high content imaging-based screen assessing 940,000 small molecules to identify those that accelerate lipid droplet clearance. Hits were validated in diverse cell lines and by counter-screening. Of the 77 validated structurally diverse hits, 24 increase autophagy flux. Herein, we highlight CCT020312 as a mammalian target of rapamycin (mTOR) inhibitor-independent autophagy activator, which should function without suppressing the immune response. CCT020312 dose-dependently reduces cytotoxic axonal mutant prion protein aggregate levels within endosomes of primary murine hippocampal neurons and normalizes axonal trafficking deficiencies. Moreover, CCT020312 robustly clears phosphorylated insoluble tau, while reducing tau-mediated neuronal stress vulnerability in patient-derived neuronal models. CCT020312 also restores lysosomal function in neurons differentiated from sporadic Alzheimer’s patients fibroblasts bearing epigenetic marks of aging. Taken together, we describe a promising strategy to uncover novel pharmacological agents that normalize cellular neurodegenerative disease pathology.

/pdf/mtor-inhibitor-independent-autophagy-activator-ameliorates-3sti3bi3.pdf

mTOR inhibitor-independent Autophagy Activator Ameliorates Tauopathy and Prionopathy Neurodegeneration Phenotypes

The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,700 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. We provided in a previous manuscript a list of chaperones and folding enzymes as well as the components that make up the machineries for protein synthesis, protein trafficking into and out of organelles, and organelle-specific degradation pathways. Here, we provide a curated list of 838 unique high-confidence components of the autophagy-lysosome pathway, one of the two major protein degradation systems in human cells.

/pdf/a-comprehensive-enumeration-of-the-human-proteostasis-i19rr6t0.pdf

A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway

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A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway