bims-proarb 2022-07-03 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022–07–03
ten papers selected by
Rich Giadone, Harvard University

Cell Non-autonomous Proteostasis Regulation in Aging and Disease.
HSP10 as a Chaperone for Neurodegenerative Amyloid Fibrils.
Editorial: The Role of Mutations, Stresses and Post-Translational Modifications in the Structure and Function of Small Heat Shock Proteins and Their Relationship with Different Human Diseases.
HDAC inhibitor and proteasome inhibitor induce cleavage and exosome-mediated secretion of HSP90 in mouse pluripotent stem cells.
Hsp multichaperone complex buffers pathologically modified Tau.
The integrated stress response remodels the microtubule organizing center to clear unfolded proteins following proteotoxic stress.
Proteome Analysis of the Soybean Nodule Phosphorus Response Mechanism and Characterization of Stress-Induced Ribosome Structural and Protein Expression Changes.
Upregulation of ribosome complexes at the blood-brain barrier in Alzheimer's disease patients.
Mitohormesis and mitochondrial dynamics in the regulation of stem cell fate.
Maintaining soluble protein homeostasis between nuclear and cytoplasmic compartments across mitosis.

Front Neurosci. 2022 ;16 878296

Cell Non-autonomous Proteostasis Regulation in Aging and Disease.

Joao Vasco Ferreira, Ana da Rosa Soares, Paulo Pereira.

  Aging is a risk factor for a number of diseases, being the more notorious ones perhaps neurodegenerative diseases such as Alzheimer's and Parkinson's. These and other age-related pathologies are often associated with accumulation of proteotoxic material inside cells, as well as with the accumulation of protein deposits extracellularly. It is widely accepted that this accumulation of toxic proteins trails a progressive decline in the mechanisms that regulate protein homeostasis, or proteostasis, during aging. However, despite significant efforts, the progress in terms of novel or improved therapies targeting accumulation of proteotoxic material has been rather limited. For example, clinical trials for new drugs aimed at treating Alzheimer's disease, by preventing accumulation of toxic proteins, have notoriously failed. On the other hand, it is becoming increasingly apparent that regulation of proteostasis is not a cell autonomous process. In fact, cells rely on complex transcellular networks to maintain tissue and organ homeostasis involving endocrine and paracrine signaling pathways. In this review we will discuss the impact of cell non-autonomous proteostasis mechanisms and their impact in aging and disease. We will focus on how transcellular proteostasis networks can shed new light into stablished paradigms about the aging of organisms.

Keywords:  misfolding; molecular chaperones; proteostasis; proteotoxicity; transcellular

DOI:  https://doi.org/10.3389/fnins.2022.878296
Front Neurosci. 2022 ;16 902600

HSP10 as a Chaperone for Neurodegenerative Amyloid Fibrils.

Johan N K Larsson, Sofie Nyström, Per Hammarström.

  Neurodegenerative diseases (NDs) are associated with accumulated misfolded proteins (MPs). MPs oligomerize and form multiple forms of amyloid fibril polymorphs that dictate fibril propagation and cellular dysfunction. Protein misfolding processes that impair protein homeostasis are implicated in onset and progression of NDs. A wide variety of molecular chaperones safeguard the cell from MP accumulation. A rather overlooked molecular chaperone is HSP10, known as a co-chaperone for HSP60. Due to the ubiquitous presence in human tissues and protein overabundance compared with HSP60, we studied how HSP10 alone influences fibril formation in vitro of Alzheimer's disease-associated Aβ1-42. At sub-stoichiometric concentrations, eukaryotic HSP10s (human and Drosophila) significantly influenced the fibril formation process and the fibril structure of Aβ1-42, more so than the prokaryotic HSP10 GroES. Similar effects were observed for prion disease-associated prion protein HuPrP90-231. Paradoxically, for a chaperone, low concentrations of HSP10 appeared to promote fibril nucleation by shortened lag-phases, which were chaperone and substrate dependent. Higher concentrations of chaperone while still sub-stoichiometric extended the nucleation and/or the elongation phase. We hypothesized that HSP10 by means of its seven mobile loops provides the chaperone with high avidity binding to amyloid fibril ends. The preserved sequence of the edge of the mobile loop GGIM(V)L (29-33 human numbering) normally dock to the HSP60 apical domain. Interestingly, this segment shows sequence similarity to amyloidogenic core segments of Aβ1-42, GGVVI (37-41), and HuPrP90-231 GGYML (126-130) likely allowing efficient competitive binding to fibrillar conformations of these MPs. Our results propose that HSP10 can function as an important molecular chaperone in human proteostasis in NDs.

Keywords:  GroES; HSP10; aggregate; amyloid; misfolding; proteostasis

DOI:  https://doi.org/10.3389/fnins.2022.902600
Front Mol Biosci. 2022 ;9 922959

Editorial: The Role of Mutations, Stresses and Post-Translational Modifications in the Structure and Function of Small Heat Shock Proteins and Their Relationship with Different Human Diseases.

Alok Kumar Panda, Ashis Biswas.



Keywords:  chaperone function; holdase; human diseases; mutations; post-translational modification (PTM); redox stress; small heat shock proteins

DOI:  https://doi.org/10.3389/fmolb.2022.922959
Biochem Biophys Res Commun. 2022 Jun 22. pii: S0006-291X(22)00911-1. [Epub ahead of print]620 29-34

HDAC inhibitor and proteasome inhibitor induce cleavage and exosome-mediated secretion of HSP90 in mouse pluripotent stem cells.

Jun-Kyu Choi, Sangkyu Park, Jeong-A Park, Ha-Eun Shin, Yeram Choi, Younghee Lee.

  Heat shock protein 90 (HSP90), one of the molecular chaperones, stabilizes several proteins necessary to maintain pluripotency of embryonic stem (ES) cells. Recently, we reported that HDAC inhibitors and proteasome inhibitors down-regulate HSP90 activity through HSP90 cleavage induced by reactive oxygen species (ROS) generation and caspase 10 activation in various cancer cells. In this study, we investigated HSP90 cleavage in mouse ES cells. HDAC inhibitors and proteasome inhibitors induced HSP90 cleavage in the mouse ES cell line R1, and the cleaved HSP90 was barely found in the cells and instead secreted out of the cells through the exosome. The HSP90 cleavage was associated with ROS generation and caspase 10 activation. In addition, HDAC inhibitor and proteasome inhibitor induced Fas expression, and the inhibition of caspase 8, a downstream molecule of Fas, blocked HSP90 cleavage. Therefore, HDAC inhibitor- and proteasome inhibitor-mediated HSP90 cleavage was induced by ROS generation and Fas expression. We observed similar results in mouse induced pluripotent stem (iPS) cells. Taken together, HSP90 cleavage was induced in mouse pluripotent cells similarly to cancer cells but differently regulated through Fas expression and exosomal secretion. These findings will be helpful in elucidating the regulation of HSP90 upon stress in pluripotent stem cells.

Keywords:  Exosome; Fas; HSP90 cleavage; Mouse ES cells; ROS; iPS cells

DOI:  https://doi.org/10.1016/j.bbrc.2022.06.057
Nat Commun. 2022 Jun 27. 13(1): 3668

Hsp multichaperone complex buffers pathologically modified Tau.

Antonia Moll, Lisa Marie Ramirez, Momchil Ninov, Juliane Schwarz, Henning Urlaub, Markus Zweckstetter.

Alzheimer's disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70/Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70/Hsp90 machinery. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on Tau's aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperone/substrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70/Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70/Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41467-022-31396-z
Elife. 2022 Jun 27. pii: e77780. [Epub ahead of print]11

The integrated stress response remodels the microtubule organizing center to clear unfolded proteins following proteotoxic stress.

Brian Hurwitz, Nicola Guzzi, Anita Gola, Vincent F Fiore, Ataman Sendoel, Maria Nikolova, Douglas Barrows, Thomas S Carroll, H Amalia Pasolli, Elaine Fuchs.

  Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells hence exposing a vulnerability in cancer that could be exploited therapeutically.

Keywords:  cancer biology; cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.77780
Front Plant Sci. 2022 ;13 908889

Proteome Analysis of the Soybean Nodule Phosphorus Response Mechanism and Characterization of Stress-Induced Ribosome Structural and Protein Expression Changes.

Yubo Yao, Hongmei Yuan, Guangwen Wu, Chunmei Ma, Zhenping Gong.

  In agroecosystems, a plant-usable form of nitrogen is mainly generated by legume-based biological nitrogen fixation, a process that requires phosphorus (P) as an essential nutrient. To investigate the physiological mechanism whereby phosphorus influences soybean nodule nitrogen fixation, soybean root nodules were exposed to four phosphate levels: 1 mg/L (P stress), 11 mg/L (P stress), 31 mg/L (Normal P), and 61 mg/L (High P) then proteome analysis of nodules was conducted to identify phosphorus-associated proteome changes. We found that phosphorus stress-induced ribosomal protein structural changes were associated with altered key root nodule protein synthesis profiles. Importantly, up-regulated expression of peroxidase was observed as an important phosphorus stress-induced nitrogen fixation-associated adaptation that supported two nodule-associated activities: scavenging of reactive oxygen species (ROS) and cell wall growth. In addition, phosphorus transporter (PT) and purple acid phosphatase (PAPs) were up-regulated that regulated phosphorus transport and utilization to maintain phosphorus balance and nitrogen fixation function in phosphorus-stressed root nodules.

Keywords:  nitrogen fixation; phosphorus; proteome; root nodule; soybean

DOI:  https://doi.org/10.3389/fpls.2022.908889
J Cereb Blood Flow Metab. 2022 Jun 29. 271678X221111602

Upregulation of ribosome complexes at the blood-brain barrier in Alzheimer's disease patients.

Masayoshi Suzuki, Kenta Tezuka, Takumi Handa, Risa Sato, Hina Takeuchi, Masaki Takao, Mitsutoshi Tano, Yasuo Uchida.

  The cerebrovascular-specific molecular mechanism in Alzheimer's disease (AD) was investigated by employing comprehensive and accurate quantitative proteomics. Highly purified brain capillaries were isolated from cerebral gray and white matter of four AD and three control donors, and examined by SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. Of the 29 ribosomal proteins that were quantified, 28 (RPLP0, RPL4, RPL6, RPL7A, RPL8, RPL10A, RPL11, RPL12, RPL14, RPL15, RPL18, RPL23, RPL27, RPL27A, RPL31, RPL35A, RPS2, RPS3, RPS3A, RPS4X, RPS7, RPS8, RPS14, RPS16, RPS20, RPS24, RPS25, and RPSA) were significantly upregulated in AD patients. This upregulation of ribosomal protein expression occurred only in brain capillaries and not in brain parenchyma. The protein expression of protein processing and N-glycosylation-related proteins in the endoplasmic reticulum (DDOST, STT3A, MOGS, GANAB, RPN1, RPN2, SEC61B, UGGT1, LMAN2, and SSR4) were also upregulated in AD brain capillaries and was correlated with the expression of ribosomal proteins. The findings reported herein indicate that the ribosome complex, the subsequent protein processing and N-glycosylation-related processes are significantly and specifically upregulated in the brain capillaries of AD patients.

Keywords:  Alzheimer’s disease; N-glycosylation; Ribosome; blood-brain barrier; protein processing

DOI:  https://doi.org/10.1177/0271678X221111602
J Cell Physiol. 2022 Jul 01.

Mitohormesis and mitochondrial dynamics in the regulation of stem cell fate.

Abolfazl Barzegari, Sobhan Aaboulhassanzadeh, Rebecca Landon, Virginie Gueguen, Anne Meddahi-Pellé, Sepideh Parvizpour, Fani Anagnostou, Graciela Pavon-Djavid.

  The ability of stem cells for self-renewing, differentiation, and regeneration of injured tissues is believed to occur via the hormetic modulation of nuclear/mitochondrial signal transductions. The evidence now indicates that in damaged tissues, the mitochondria set off the alarm under oxidative stress conditions, hence they are the central regulators of stem cell fate decisions. This review aimed to provide an update to a broader concept of stem cell fate in stress conditions of damaged tissues, and insights for the mitochondrial hormesis (mitohormesis), including the integrated stress response (ISR), mitochondrial dynamics, mitochondria uncoupling, unfolded protein response, and mitokines, with implications for the control of stem cells programing in a successful clinical cell therapy.

Keywords:  hypoxia; integrated stress response; mitohormesis; mitokines; oxidative stress; stem cell

DOI:  https://doi.org/10.1002/jcp.30820
Trends Cell Biol. 2022 Jun 28. pii: S0962-8924(22)00141-6. [Epub ahead of print]

Maintaining soluble protein homeostasis between nuclear and cytoplasmic compartments across mitosis.

Sabina Y van der Zanden, Marlieke L M Jongsma, Anna C M Neefjes, Ilana Berlin, Jacques Neefjes.

  The nuclear envelope (NE) is central to the architecture of eukaryotic cells, both as a physical barrier separating the nucleus from the cytoplasm and as gatekeeper of selective transport between them. However, in open mitosis, the NE fragments to allow for spindle formation and segregation of chromosomes, resulting in intermixing of nuclear and cytoplasmic soluble fractions. Recent studies have shed new light on the mechanisms driving reinstatement of soluble proteome homeostasis following NE reformation in daughter cells. Here, we provide an overview of how mitotic cells confront this challenge to ensure continuity of basic cellular functions across generations and elaborate on the implications for the proteasome - a macromolecular machine that functions in both cytoplasmic and nuclear compartments.

Keywords:  chromatin condensation; mitosis; nuclear envelope; proteasome; protein homeostasis

DOI:  https://doi.org/10.1016/j.tcb.2022.06.002