bims-proarb 2021-09-26 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2021–09–26
eleven papers selected by
Rich Giadone, Harvard University

Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer's Disease.
ATF6 is essential for human cone photoreceptor development.
Expanding the Family of Extracellular Chaperones: Identification of Human Plasma Proteins with Chaperone Activity.
Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.
ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.
Protein structure and aggregation: a marriage of necessity ruled by aggregation gatekeepers.
Necroptosis activates UPR sensors without disrupting their binding with GRP78.
Elongin functions as a loading factor for Mediator at ATF6α-regulated ER stress response genes.
A new mouse model to study neuronal proteostasis.
Activation of Autophagy Ameliorates Age-Related Neurogenesis Decline and Neurodysfunction in Adult Mice.
Delineating the complex mechanistic interplay between NF-κβ driven mTOR depedent autophagy and monocyte to macrophage differentiation: A functional perspective.

Front Cell Dev Biol. 2021 ;9 745011

Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer's Disease.

Xun Gao, Yuanyuan Xu.

  Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive cognitive impairment and memory loss. So far, the pathogenesis of AD has not been fully understood. Research have shown that endoplasmic reticulum (ER) stress and unfolded protein response (UPR) participate in the occurrence and development of AD. Furthermore, various studies, both in vivo and in vitro, have shown that targeting ER stress and ER stress-mediated apoptosis contribute to the recovery of AD. Thus, targeting ER stress and ER stress-mediated apoptosis may be effective for treating AD. In this review, the molecular mechanism of ER stress and ER stress-mediated apoptosis, as well as the therapeutic effects of some natural compounds and small molecule inhibitors targeting ER stress and ER stress-mediated apoptosis in AD will be introduced.

Keywords:  Alzheimer’s disease; apoptosis; endoplasmic reticulum stress; neuroprotection; unfolded protein response

DOI:  https://doi.org/10.3389/fcell.2021.745011
Proc Natl Acad Sci U S A. 2021 Sep 28. pii: e2103196118. [Epub ahead of print]118(39):

ATF6 is essential for human cone photoreceptor development.

Heike Kroeger, Julia M D Grandjean, Wei-Chieh Jerry Chiang, Daphne D Bindels, Rebecca Mastey, Jennifer Okalova, Amanda Nguyen, Evan T Powers, Jeffery W Kelly, Neil J Grimsey, Michel Michaelides, Joseph Carroll, R Luke Wiseman, Jonathan H Lin.

  Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.

Keywords:  ATF6 signaling; achromatopsia; cone photoreceptors; retinal organoids; stem cell biology

DOI:  https://doi.org/10.1073/pnas.2103196118
Protein Sci. 2021 Sep 23.

Expanding the Family of Extracellular Chaperones: Identification of Human Plasma Proteins with Chaperone Activity.

Nicholas J Geraghty, Sandeep Satapathy, Megan Kelly, Flora Cheng, Albert Lee, Mark R Wilson.

  Proteostasis, the balance of protein synthesis, folding and degradation, is essential to maintain cellular function and viability, and the many known intracellular chaperones are recognised as playing key roles in sustaining life. In contrast, the identity of constitutively secreted extracellular chaperones (ECs) and their physiological roles in extracellular proteostasis is less completely understood. We designed and implemented a novel strategy, based on the well-known propensity of chaperones to bind to regions of hydrophobicity exposed on misfolding proteins, to discover new ECs present in human blood. We used a destabilised protein that misfolds at 37 o C as "bait" to bind to potential ECs in human serum and captured the complexes formed on magnetic beads. Proteins eluted from the beads were identified by mass spectrometry and a group of seven abundant serum proteins were selected for in vitro analysis of chaperone activity. Five of these proteins were shown to specifically inhibit protein aggregation. Vitronectin and plasminogen activator-3 inhibited both the in vitro aggregation of the Alzheimer's β peptide (Aβ1-42 ) to form fibrillar amyloid, and the aggregation of citrate synthase (CS) to form unstructured (amorphous) aggregates. In contrast, prothrombin, C1r, and C1s inhibited the aggregation of Aβ1-42 but did not inhibit CS aggregation. This study thus identified five novel and abundant putative ECs which may play important roles in the maintenance of extracellular proteostasis, and which apparently have differing abilities to inhibit the amorphous and amyloid-forming protein aggregation pathways. This article is protected by copyright. All rights reserved.

Keywords:  C1r; C1s; Extracellular Chaperones; Plasminogen Activator Inhibitor 3; Proteostasis; Prothrombin; Vitronectin

DOI:  https://doi.org/10.1002/pro.4189
Aging Cell. 2021 Sep 23. e13467

Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.

Jae Min Cho, Seul-Ki Park, Rajeshwary Ghosh, Kellsey Ly, Caroline Ramous, Lauren Thompson, Michele Hansen, Maria Sara de Lima Coutinho Mattera, Karla Maria Pires, Maroua Ferhat, Sohom Mookherjee, Kevin J Whitehead, Kandis Carter, Márcio Buffolo, Sihem Boudina, J David Symons.

  Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice. As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice (all p < 0.05). To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old-ETR vs. old-SED mice. These data provide the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.

Keywords:  aging; cardiac function; exercise; protein aggregates

DOI:  https://doi.org/10.1111/acel.13467
Nat Chem Biol. 2021 Sep 23.

ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.

Hannah C Feldman, Rajarshi Ghosh, Vincent C Auyeung, James L Mueller, Jae-Hong Kim, Zachary E Potter, Venkata N Vidadala, B Gayani K Perera, Alina Olivier, Bradley J Backes, Julie Zikherman, Feroz R Papa, Dustin J Maly.

The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing β-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.

DOI: https://doi.org/10.1038/s41589-021-00852-0
Trends Biochem Sci. 2021 Sep 21. pii: S0968-0004(21)00190-0. [Epub ahead of print]

Protein structure and aggregation: a marriage of necessity ruled by aggregation gatekeepers.

Bert Houben, Frederic Rousseau, Joost Schymkowitz.

  Protein aggregation propensity is a pervasive and seemingly inescapable property of proteomes. Strikingly, a significant fraction of the proteome is supersaturated, meaning that, for these proteins, their native conformation is less stable than the aggregated state. Maintaining the integrity of a proteome under such conditions is precarious and requires energy-consuming proteostatic regulation. Why then is aggregation propensity maintained at such high levels over long evolutionary timescales? Here, we argue that the conformational stability of the native and aggregated states are correlated thermodynamically and that codon usage strengthens this correlation. As a result, the folding of stable proteins requires kinetic control to avoid aggregation, provided by aggregation gatekeepers. These unique residues are evolutionarily selected to kinetically favor native folding, either on their own or by coopting chaperones.

Keywords:  amyloid; kinetic partitioning; protein aggregation; protein stability; protein structure; proteostasis

DOI:  https://doi.org/10.1016/j.tibs.2021.08.010
Proc Natl Acad Sci U S A. 2021 09 28. pii: e2110476118. [Epub ahead of print]118(39):

Necroptosis activates UPR sensors without disrupting their binding with GRP78.

Wei Liang, Weiwei Qi, Yang Geng, Linhan Wang, Jing Zhao, Kezhou Zhu, Guowei Wu, Zairong Zhang, Heling Pan, Lihui Qian, Junying Yuan.

  Necroptosis is a form of regulated necrosis mediated by the formation of the necrosome, composed of the RIPK1/RIPK3/MLKL complex. Here, we developed a proximity ligation assay (PLA) that allows in situ visualization of necrosomes in necroptotic cells and in vivo. Using PLA assay, we show that necrosomes can be found in close proximity to the endoplasmic reticulum (ER). Furthermore, we show that necroptosis activates ER stress sensors, PERK, IRE1α, and ATF6 in a RIPK1-RIPK3-MLKL axis-dependent manner. Activated MLKL can be translocated to the ER membrane to directly initiate the activation of ER stress signaling. The activation of IRE1α in necroptosis promotes the splicing of XBP1, and the subsequent incorporation of spliced XBP1 messenger RNA (mRNA) into extracellular vesicles (EVs). Finally, we show that unlike that of a conventional ER stress response, necroptosis promotes the activation of unfolded protein response (UPR) sensors without affecting their binding of GRP78. Our study reveals a signaling pathway that links MLKL activation in necroptosis to an unconventional ER stress response.

Keywords:  ER stress; IRE1α; PERK; UPR sensors; necroptosis

DOI:  https://doi.org/10.1073/pnas.2110476118
Proc Natl Acad Sci U S A. 2021 09 28. pii: e2108751118. [Epub ahead of print]118(39):

Elongin functions as a loading factor for Mediator at ATF6α-regulated ER stress response genes.

Yanfeng He, Shigeo Sato, Chieri Tomomori-Sato, Shiyuan Chen, Zach H Goode, Joan W Conaway, Ronald C Conaway.

  The bZIP transcription factor ATF6α is a master regulator of endoplasmic reticulum (ER) stress response genes. In this report, we identify the multifunctional RNA polymerase II transcription factor Elongin as a cofactor for ATF6α-dependent transcription activation. Biochemical studies reveal that Elongin functions at least in part by facilitating ATF6α-dependent loading of Mediator at the promoters and enhancers of ER stress response genes. Depletion of Elongin from cells leads to impaired transcription of ER stress response genes and to defects in the recruitment of Mediator and its CDK8 kinase subunit. Taken together, these findings bring to light a role for Elongin as a loading factor for Mediator during the ER stress response.

Keywords:  Mediator; RNA polymerase II; enhancer; transcription

DOI:  https://doi.org/10.1073/pnas.2108751118
Lab Anim (NY). 2021 Oct;50(10): 281

A new mouse model to study neuronal proteostasis.

Alexandra Le Bras.

DOI: https://doi.org/10.1038/s41684-021-00863-3
Stem Cell Rev Rep. 2021 Sep 21.

Activation of Autophagy Ameliorates Age-Related Neurogenesis Decline and Neurodysfunction in Adult Mice.

Na Yang, Xueqin Liu, Xiaojie Niu, Xiaoqiang Wang, Rong Jiang, Na Yuan, Jianrong Wang, Chengwu Zhang, Kah-Leong Lim, Li Lu.

  Adult neurogenesis is the ongoing generation of functional new neurons from neural progenitor cells (NPCs) in the mammalian brain. However, this process declines with aging, which is implicated in the recession of brain function and neurodegeneration. Understanding the mechanism of adult neurogenesis and stimulating neurogenesis will benefit the mitigation of neurodegenerative diseases. Autophagy, a highly conserved process of cellular degradation, is essential for maintaining cellular homeostasis and normal function. Whether and how autophagy affects adult neurogenesis remains poorly understood. In present study, we revealed a close connection between impaired autophagy and adult neurogenetic decline. Expression of autophagy-related genes and autophagic activity were significantly declined in the middle-adult subventricular/subgranular zone (SVZ/SGZ) homogenates and cultured NPCs, and inhibiting autophagy by siRNA interference resulted in impaired proliferation and differentiation of NPCs. Conversely, stimulating autophagy by rapamycin not only revitalized the viability of middle-adult NPCs, but also facilitated the neurogenesis in middle-adult SVZ/SGZ. More importantly, autophagic activation by rapamycin also ameliorated the olfactory sensitivity and cognitional capacities in middle-adult mice. Taken together, our results reveal that compromised autophagy is involved in the decline of adult neurogenesis, which could be reversed by autophagy activation. It also shed light on the regulation of adult neurogenesis and paves the way for developing a therapeutic strategy for aging and neurodegenerative diseases.

Keywords:  Adult neurogenesis; Autophagy; Neural progenitor cell; Rapamycin; mTOR

DOI:  https://doi.org/10.1007/s12015-021-10265-0
Cell Signal. 2021 Sep 18. pii: S0898-6568(21)00239-4. [Epub ahead of print] 110150

Delineating the complex mechanistic interplay between NF-κβ driven mTOR depedent autophagy and monocyte to macrophage differentiation: A functional perspective.

Anindita Bhattacharya, Purnam Ghosh, Arpana Singh, Arnab Ghosh, Arghya Bhowmick, Deepak Kumar Sinha, Abhrajyoti Ghosh, Prosenjit Sen.

  Autophagy is an extremely essential cellular process aimed to clear redundant and damaged materials, namely organelles, protein aggregates, invading pathogens, etc. through the formation of autophagosomes which are ultimately targeted to lysosomal degradation. In this study, we demonstrated that mTOR dependent classical autophagy is ubiquitously triggered in differentiating monocytes. Moreover, autophagy plays a decisive role in sustaining the process of monocyte to macrophage differentiation. We have delved deeper into understanding the underlying mechanistic complexities that trigger autophagy during differentiation. Intrigued by the significant difference between the protein profiles of monocytes and macrophages, we investigated to learn that autophagy directs monocyte differentiation via protein degradation. Further, we delineated the complex cross-talk between autophagy and cell-cycle arrest in differentiating monocytes. This study also inspects the contribution of adhesion on various steps of autophagy and its ultimate impact on monocyte differentiation. Our study reveals new mechanistic insights into the process of autophagy associated with monocyte differentiation and would undoubtedly help to understand the intricacies of the process better for the effective design of therapeutics as autophagy and autophagy-related processes have enormous importance in human patho-physiology.

Keywords:  Adhesion; Autophagy; Differentiation; Macrophage; Monocyte

DOI:  https://doi.org/10.1016/j.cellsig.2021.110150