bims-proarb 2022-03-13 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022–03–13
ten papers selected by
Rich Giadone, Harvard University

Mechanisms tailoring the expression of heat shock proteins to proteostasis challenges.
Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress.
Modulation of the Ubiquitin-Proteasome System Restores Plasticity in Hippocampal Pyramidal Neurons of the APP/PS1 Alzheimer's Disease-Like Mice.
Genome-wide transcript and protein analysis highlights the role of protein homeostasis in the aging mouse heart.
Reversible phase separation of HSF1 is required for an acute transcriptional response during heat shock.
Ageing induces tissue-specific transcriptomic changes in Caenorhabditis elegans.
Exposing the Brain Proteomic Signatures of Alzheimer's Disease in Diverse Racial Groups: Leveraging Multiple Data Sets and Machine Learning.
Kap1 Regulates the Stability of Lin28A in Embryonic Stem Cells.
A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson disease.
Distinct and diverse chromatin-proteomes of ageing mouse organs reveal protein signatures that correlate with physiological functions.

J Biol Chem. 2022 Mar 03. pii: S0021-9258(22)00236-8. [Epub ahead of print] 101796

Mechanisms tailoring the expression of heat shock proteins to proteostasis challenges.

Lokha R Alagar Boopathy, Suleima Jacob-Tomas, Célia Alecki, Maria Vera.

  All cells possess an internal stress response to cope with environmental and pathophysiological challenges. Upon stress, cells reprogram their molecular functions to activate a survival mechanism known as the heat shock response (HSR), which mediates the rapid induction of molecular chaperones such as the heat shock proteins (HSPs). This potent production overcomes the general suppression of gene expression and results in high levels of HSPs to subsequently refold or degrade misfolded proteins. Once the damage or stress is repaired or removed, cells terminate the production of HSPs and resume regular functions. Thus, fulfillment of the stress response requires swift and robust coordination between stress response activation and completion that is determined by the status of the cell. In recent years, single-cell fluorescence microscopy techniques have begun to be used in unravelling HSP the gene expression pathways, from DNA transcription to mRNA degradation. In this review, we will address the molecular mechanisms in different organisms and cell types that coordinate the expression of HSPs to activate signaling networks that act to reprogram gene transcription, mRNA translation and decay, and ensure protein quality control.

Keywords:  Heat Shock Factor 1; Heat Shock Proteins; Heat Shock Response; acclimation; gene expression; mRNA decay; proteostasis; stress-regulated translation

DOI:  https://doi.org/10.1016/j.jbc.2022.101796
Cells. 2022 Mar 01. pii: 851. [Epub ahead of print]11(5):

Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress.

Yanan Li, Shujing Li, Huijian Wu.

  In response to environmental stimuli, cells make a series of adaptive changes to combat the injury, repair the damage, and increase the tolerance to the stress. However, once the damage is too serious to repair, the cells will undergo apoptosis to protect the overall cells through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions to form protein aggregation, which may ultimately produce serious damage to the cells. Ubiquitin plays an important role in the degradation of these unnatural proteins by tagging with ubiquitin chains in the ubiquitin-proteasome or autophagy system. If the two processes fail to eliminate the abnormal protein aggregates, the cells will move to apoptosis and death. Dysregulation of ubiquitin-proteasome system (UPS) and autophagy may result in the development of numerous diseases. This review focuses on the molecular mechanisms of UPS and autophagy in clearance of intracellular protein aggregates, and the relationship between dysregulation of ubiquitin network and diseases.

Keywords:  autophagy; cell stress; endoplasmic reticulum stress; ubiquitin; ubiquitin–proteasome system; unfolded protein response

DOI:  https://doi.org/10.3390/cells11050851
J Alzheimers Dis. 2022 Feb 28.

Modulation of the Ubiquitin-Proteasome System Restores Plasticity in Hippocampal Pyramidal Neurons of the APP/PS1 Alzheimer's Disease-Like Mice.

Kumar Krishna-K, Thomas Behnisch, Sreedharan Sajikumar.

  Alzheimer's disease (AD) is characterized by memory and cognitive deficits that in part are related to a diminished ability to activity-dependent synaptic plasticity. In AD, an attenuated long-term potentiation has been correlated with a deficit of synaptic plasticity-relevant proteins and protein turnover. The ubiquitin-proteasome system (UPS) critically regulates the protein turnover and contributes to dynamic changes of the protein milieu within synapses. In AD, UPS aberration has been implicated in inadequate proteostasis and synaptic malfunction. However, here we show that the inhibition of proteasome-mediated protein degradation by MG132 or lactacystin restored an impaired activity-dependent synaptic plasticity in an AD-like mouse model. In this whole-cell voltage-clamp study, we provided evidence that an amelioration of long-term plasticity by modulating UPS activity in pyramidal neurons.

Keywords:  Alzheimer’s disease; MG132; hippocampus; lactacystin; long-term potentiation; protein degradation; proteostasis; synaptic plasticity; ubiquitin-proteasome system

DOI:  https://doi.org/10.3233/JAD-215718
Genome Res. 2022 Mar 11. pii: gr.275672.121. [Epub ahead of print]

Genome-wide transcript and protein analysis highlights the role of protein homeostasis in the aging mouse heart.

Isabela Gerdes Gyuricza, Joel M Chick, Gregory R Keele, Andrew G Deighan, Steven C Munger, Ron C Korstanje, Steven P Gygi, Gary A Churchill.

Investigation of the molecular mechanisms of aging in the human heart is challenging due to confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyze transcriptome and proteome data from 185 genetically diverse male and female mice at ages 6, 12 and 18 months to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal activation of pathways related to exocytosis and cellular transport with age, while processes involved in protein folding decrease with age. Additional changes are apparent only in the protein data including reduced fatty acid oxidation and increased autophagy. For proteins that form complexes, we see a decline in correlation between their component subunits with age, suggesting age-related loss of stoichiometry. The most affected complexes are themselves involved in protein homeostasis, which potentially contributes to a cycle of progressive breakdown in protein quality control with age. Our findings highlight the important role of post-transcriptional regulation in aging. In addition, we identify genetic loci that modulate age-related changes in protein homeostasis, suggesting that genetic variation can alter the molecular aging process.

DOI: https://doi.org/10.1101/gr.275672.121
Nat Cell Biol. 2022 Mar 07.

Reversible phase separation of HSF1 is required for an acute transcriptional response during heat shock.

Hongchen Zhang, Shipeng Shao, Yong Zeng, Xiaotian Wang, Yizhi Qin, Qiunan Ren, Shengqi Xiang, Yuxin Wang, Junyu Xiao, Yujie Sun.

Heat-shock transcription factor 1 (HSF1) orchestrates the fast and vast cellular response to heat shock through increased expression of heat-shock proteins. However, how HSF1 rapidly and reversibly regulates transcriptional reprogramming remains poorly defined. Here by combining super-resolution imaging, in vitro reconstitution and high-throughput sequencing, we reveal that HSF1 forms small nuclear condensates via liquid-liquid phase separation at heat-shock-protein gene loci and enriches multiple transcription apparatuses through co-phase separation to promote the transcription of target genes. Furthermore, the phase-separation capability of HSF1 is fine-tuned through phosphorylation at specific sites within the regulatory domain. Last, we discovered that HSP70 disperses HSF1 condensates to attenuate transcription following the cessation of heat shock and further prevents the gel-like phase transition of HSF1 under extended heat-shock stress. Our work reveals an inducible and reversible phase-separation feedback mechanism for dynamic regulation of HSF1 activity to drive the transcriptional response and maintain protein homeostasis during acute stress.

DOI: https://doi.org/10.1038/s41556-022-00846-7
EMBO J. 2022 Mar 07. e109633

Ageing induces tissue-specific transcriptomic changes in Caenorhabditis elegans.

Xueqing Wang, Quanlong Jiang, Yuanyuan Song, Zhidong He, Hongdao Zhang, Mengjiao Song, Xiaona Zhang, Yumin Dai, Oezlem Karalay, Christoph Dieterich, Adam Antebi, Ligang Wu, Jing-Dong J Han, Yidong Shen.

  Ageing is a complex process with common and distinct features across tissues. Unveiling the underlying processes driving ageing in individual tissues is indispensable to decipher the mechanisms of organismal longevity. Caenorhabditis elegans is a well-established model organism that has spearheaded ageing research with the discovery of numerous genetic pathways controlling its lifespan. However, it remains challenging to dissect the ageing of worm tissues due to the limited description of tissue pathology and access to tissue-specific molecular changes during ageing. In this study, we isolated cells from five major tissues in young and old worms and profiled the age-induced transcriptomic changes within these tissues. We observed a striking diversity of ageing across tissues and identified different sets of longevity regulators therein. In addition, we found novel tissue-specific factors, including irx-1 and myrf-2, which control the integrity of the intestinal barrier and sarcomere structure during ageing respectively. This study demonstrates the complexity of ageing across worm tissues and highlights the power of tissue-specific transcriptomic profiling during ageing, which can serve as a resource to the field.

Keywords:   Caenorhabditis elegans ; ageing; tissue; transcription factor; transcriptomic change

DOI:  https://doi.org/10.15252/embj.2021109633
J Proteome Res. 2022 Mar 11.

Exposing the Brain Proteomic Signatures of Alzheimer's Disease in Diverse Racial Groups: Leveraging Multiple Data Sets and Machine Learning.

Heather Desaire, Kaitlyn E Stepler, Renã A S Robinson.

  Recent studies have highlighted that the proteome can be used to identify potential biomarker candidates for Alzheimer's disease (AD) in diverse cohorts. Furthermore, the racial and ethnic background of participants is an important factor to consider to ensure the effectiveness of potential biomarkers for representative populations. A promising approach to survey potential biomarker candidates for diagnosing AD in diverse cohorts is the application of machine learning to proteomics data sets. Herein, we leveraged six existing bottom-up proteomics data sets, which included non-Hispanic White, African American/Black, and Hispanic participants, to study protein changes in AD and cognitively unimpaired participants. Machine learning models were applied to these data sets and resulted in the identification of amyloid-β precursor protein (APP) and heat shock protein β-1 (HSPB1) as two proteins that have high ability to distinguish AD; however, each protein's performance varied based upon the racial and ethnic background of the participants. HSPB1 particularly was helpful for generating high areas under the curve (AUCs) for African American/Black participants. Overall, HSPB1 improved the performance of the machine learning models when combined with APP and/or participant age and is a potential candidate that should be further explored in AD biomarker discovery efforts.

Keywords:  APP; AUCs; African American; Alzheimer’s disease; amyloid-β precursor protein; heat shock protein; machine learning; proteomics

DOI:  https://doi.org/10.1021/acs.jproteome.1c00966
Stem Cells. 2022 Mar 09. pii: sxac010. [Epub ahead of print]

Kap1 Regulates the Stability of Lin28A in Embryonic Stem Cells.

Hye Ji Moon, Na Yeon Lee, Eun Kyoung Do, Seo Yul Lee, Gyu Tae Park, Jae Kyong Lim, Jeong Kon Seo, Jae Ho Kim.

  Lin28A is an RNA-binding protein that controls mammalian development and maintenance of the pluripotency of embryonic stem cells (ESCs) via regulating the processing of the microRNA let-7. Lin28A is highly expressed in ESCs, and ectopic expression of this protein facilitates reprogramming of somatic cells to induced pluripotent stem cells. However, the mechanisms underlying the post-translational regulation of Lin28A protein stability in ESCs remain unclear. In the present study, we identified Kap1 (KRAB-associated protein 1) as a novel Lin28A-binding protein using affinity purification and mass spectrometry. Kap1 specifically interacted with the N-terminal region of Lin28A through its coiled-coil domain. Kap1 overexpression significantly attenuated Lin28A ubiquitination and increased its stability. However, small interfering RNA-mediated knockdown of Kap1 promoted the ubiquitination of Lin28A, leading to its proteasomal degradation. Trim71, an E3 ubiquitin ligase, induced Lin28A degradation and Kap1 knockdown accelerated the Trim71-dependent degradation of Lin28A. Mutation of the lysine 177 residue of Lin28A to arginine abrogated the ubiquitination and degradation of Lin28A which were accelerated by Kap1 silencing. Moreover, Kap1 overexpression led to the accumulation of Lin28A in the cytoplasm, but not in the nucleus, and reduced the levels of let-7 subtypes. These results suggest that Kap1 plays a key role in regulation of the stability of Lin28A by modulating the Trim71-mediated ubiquitination and subsequent degradation of Lin28A, thus playing a pivotal role in the regulation of ESC self-renewal and pluripotency.

Keywords:  Kap1; Lin28; embryonic stem cells; protein stability; ubiquitination

DOI:  https://doi.org/10.1093/stmcls/sxac010
PLoS Biol. 2022 Mar 09. 20(3): e3001578

A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson disease.

Morgan Bérard, Razan Sheta, Sarah Malvaut, Raquel Rodriguez-Aller, Maxime Teixeira, Walid Idi, Roxanne Turmel, Melanie Alpaugh, Marilyn Dubois, Manel Dahmene, Charleen Sales, Jérôme Lamontagne-Proulx, Marie-Kim St-Pierre, Omid Tavassoly, Wen Luo, Esther Del Cid-Pellitero, Raza Qazi, Jae-Woong Jeong, Thomas M Durcan, Luc Vallières, Marie-Eve Tremblay, Denis Soulet, Martin Lévesque, Francesca Cicchetti, Edward A Fon, Armen Saghatelyan, Abid Oueslati.

Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.

DOI: https://doi.org/10.1371/journal.pbio.3001578
Elife. 2022 Mar 08. pii: e73524. [Epub ahead of print]11

Distinct and diverse chromatin-proteomes of ageing mouse organs reveal protein signatures that correlate with physiological functions.

Giorgio Oliviero, Sergey Kovalchuk, Adelina Rogowska-Wrzesinska, Veit Schwämmle, Ole N Jensen.

  Temporal molecular changes in ageing mammalian organs are of relevance to disease etiology because many age-related diseases are linked to changes in the transcriptional and epigenetic machinery that regulate gene expression. We performed quantitative proteome analysis of chromatin-enriched protein extracts to investigate the dynamics of the chromatin-proteomes of the mouse brain, heart, lung, kidney, liver, and spleen at 3, 5, 10, and 15 months of age. Each organ exhibited a distinct chromatin-proteome and sets of unique proteins. The brain and spleen chromatin-proteomes were the most extensive, diverse, and heterogenous among the six organs. The spleen chromatin proteome appeared static during the lifespan, presenting a young phenotype that reflects the permanent alertness state and important role of this organ in physiological defense and immunity. We identified a total of 5928 proteins, including 2472 nuclear or chromatin associated proteins across the six mouse organs. Up to 3125 proteins were quantified in each organ demonstrating distinct and organ-specific temporal protein expression timelines and regulation at the post-translational level. Bioinformatics meta-analysis of these chromatin proteomes revealed distinct physiological and ageing-related features for each organ. Our results demonstrate the efficiency of organelle specific proteomics for in vivo studies of a model organism and consolidate the hypothesis that chromatin-associated proteins are involved in distinct and specific physiological functions in ageing organs.

Keywords:  cell biology; developmental biology; mouse

DOI:  https://doi.org/10.7554/eLife.73524