Effects of Protein Quality Control Machinery on Protein Homeostasis

Abstract Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83/miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans. Upregulated in the intestine by hsf-1/HSF1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5/MCOLN, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity. These findings thus identify a microRNA-based mechanism to coordinate the decreasing macroautophagy in various tissues with age.

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The role of protein quality control in mitochondrial protein homeostasis under oxidative stress

PROTEOMICS ◽

10.1002/pmic.200800619 ◽

2010 ◽

Vol 10 (7) ◽

pp. 1426-1443 ◽

Cited By ~ 66

Author(s):

Tom Bender ◽

Claudia Leidhold ◽

Thomas Ruppert ◽

Sebastian Franken ◽

Wolfgang Voos

Keyword(s):

Oxidative Stress ◽

Quality Control ◽

Protein Quality ◽

Mitochondrial Protein ◽

Protein Quality Control ◽

Protein Homeostasis

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Mechanismen und Funktionen von bakteriellen AAA+Entfaltungsmaschinen

BIOspektrum ◽

10.1007/s12268-021-1515-7 ◽

2021 ◽

Vol 27 (1) ◽

pp. 22-24

Author(s):

Axel Mogk

Keyword(s):

Quality Control ◽

Drug Target ◽

Protein Quality ◽

Protein Quality Control ◽

Stress Conditions ◽

Misfolded Proteins ◽

Antibacterial Drug ◽

Protein Homeostasis ◽

Antibacterial Drug Target

AbstractBacterial AAA+ proteins play crucial roles in proteostasis networks and ensure protein homeostasis during stress conditions. They function as ATP-dependent components of proteolytic complexes degrading misfolded proteins or as disaggregases reactivating aggregated proteins. AAA+ proteins generate an ATP-fueled threading force driving substrate unfolding and translocation. Their central functions in protein quality control qualify them as antibacterial drug target.

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Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery

Biochemical Journal ◽

10.1042/bcj20190497 ◽

2020 ◽

Vol 477 (18) ◽

pp. 3471-3497 ◽

Cited By ~ 1

Author(s):

Tongyin Zheng ◽

Yiran Yang ◽

Carlos A. Castañeda

Keyword(s):

Quality Control ◽

Rna Binding ◽

Protein Quality ◽

Rna Binding Proteins ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Protein Homeostasis ◽

Intrinsically Disordered ◽

Structure Dynamics ◽

And Function

Cells rely on protein homeostasis to maintain proper biological functions. Dysregulation of protein homeostasis contributes to the pathogenesis of many neurodegenerative diseases and cancers. Ubiquilins (UBQLNs) are versatile proteins that engage with many components of protein quality control (PQC) machinery in cells. Disease-linked mutations of UBQLNs are most commonly associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. UBQLNs play well-established roles in PQC processes, including facilitating degradation of substrates through the ubiquitin–proteasome system (UPS), autophagy, and endoplasmic-reticulum-associated protein degradation (ERAD) pathways. In addition, UBQLNs engage with chaperones to sequester, degrade, or assist repair of misfolded client proteins. Furthermore, UBQLNs regulate DNA damage repair mechanisms, interact with RNA-binding proteins (RBPs), and engage with cytoskeletal elements to regulate cell differentiation and development. Important to the myriad functions of UBQLNs are its multidomain architecture and ability to self-associate. UBQLNs are linked to numerous types of cellular puncta, including stress-induced biomolecular condensates, autophagosomes, aggresomes, and aggregates. In this review, we focus on deciphering how UBQLNs function on a molecular level. We examine the properties of oligomerization-driven interactions among the structured and intrinsically disordered segments of UBQLNs. These interactions, together with the knowledge from studies of disease-linked mutations, provide significant insights to UBQLN structure, dynamics and function.

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Protein quality control: from mechanism to disease

Cell Stress and Chaperones ◽

10.1007/s12192-019-01040-9 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1013-1026

Author(s):

Harm H. Kampinga ◽

Matthias P. Mayer ◽

Axel Mogk

Keyword(s):

Quality Control ◽

Protein Quality ◽

Acute Stress ◽

Protein Quality Control ◽

Cellular Protein ◽

Stress Conditions ◽

Protein Homeostasis ◽

Physiological Conditions ◽

Age Related ◽

Medical Translation

Abstract The cellular protein quality control machinery with its central constituents of chaperones and proteases is vital to maintain protein homeostasis under physiological conditions and to protect against acute stress conditions. Imbalances in protein homeostasis also are keys to a plethora of genetic and acquired, often age-related, diseases as well as aging in general. At the EMBO Workshop, speakers covered all major aspects of cellular protein quality control, from basic mechanisms at the molecular, cellular, and organismal level to medical translation. In this report, the highlights of the meeting will be summarized.

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Programmed trade-offs in protein folding networks

10.1101/2020.04.07.030056 ◽

2020 ◽

Author(s):

Sebastian Pechmann

Keyword(s):

Quality Control ◽

Protein Folding ◽

Protein Quality ◽

De Novo ◽

Protein Quality Control ◽

Cellular Protein ◽

Amino Acid Sequences ◽

Integrated Analysis ◽

Protein Homeostasis ◽

Trade Offs

Maintaining protein homeostasis, i.e. a folded and functional proteome, depends on the efficient allocation of cellular protein quality control resources. Decline and dysregulation of protein homeostasis are directly associated to conditions of aging and neurodegeneration. Molecular chaperones as specialized protein quality control enzymes form the core of protein homeostasis. However, how chaperones selectively interact with their substrate proteins thus allocate their overall limited capacity remains poorly understood. Here, I present an integrated analysis of sequence and structural determinants that define interactions of the Saccharomyces cerevisiae Hsp70 Ssb. Structural homologues that differentially interact with Ssb for de novo folding were found to systematically differ in complexity of their folding landscapes, selective use of nonoptimal codons, and presence of short discriminative sequences. All analyzed characteristics contributed to the prediction of Ssb interactions in highly complementary manner, highlighting pervasive trade-offs in chaperone-assisted protein folding landscapes. However, short discriminative sequences were found to contribute by far the strongest signal towards explaining Ssb interactions. This observation suggested that some chaperone interactions may be directly programmed in the amino acid sequences rather than responding to folding challenges, possibly for regulatory advantages.

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Protein homeostasis limiting cancer

Science Signaling ◽

10.1126/scisignal.aaf2516 ◽

2016 ◽

Vol 9 (411) ◽

pp. ec12-ec12

Author(s):

Wei Wong

Keyword(s):

Bone Marrow ◽

Quality Control ◽

Protein Quality ◽

Kinase Inhibitor ◽

Myeloproliferative Neoplasms ◽

Protein Quality Control ◽

Protein Homeostasis ◽

Dependent Manner ◽

Mature Form ◽

Link Type

There is interest in targeting protein quality control pathways that ensure refolding or elimination of misfolded proteins to kill cancer cells. Osorio et al. identified a role for AIRAPL (an ortholog of AIP-1, which is involved in protein quality control pathways in Caenorhabditis elegans) in myeloproliferative neoplasms, a group of diseases in which the production of blood cells in the bone marrow is increased. Mice lacking Zfand2b (the gene encoding AIRAPL) developed hematological symptoms characteristic of myeloproliferative neoplasms, such as splenomegaly and expansion of various myeloid lineages. Western blot analysis of bone marrow from Zfand2b–/– mice revealed an increase in the total abundance and phosphorylation of insulin/insulin-like growth factor 1 receptor (IGF1R), a kinase that activates cell growth and proliferation. In HEK-293T cells, overexpression of AIRAPL reduced IGF1R abundance in a proteasome-dependent manner. Furthermore, exogenous AIRAPL interacted with pro-IGF1R rather than mature IGF1R, and knockout of endogenous AIRAPL resulted in an increase in the abundance of mature IGF1R, suggesting that AIRAPL triggered the proteasomal degradation of pro-IGF1R before it could undergo processing to the mature form. Igf1r haploinsufficiency in Zfand2b–/– mice or treatment of Zfand2b–/– mice with a kinase inhibitor of IGF1R prevented or attenuated the development of hematological symptoms seen in Zfand2b–/– mice. In addition, hematological symptoms were improved in mice that are a model of a specific type of myeloproliferative neoplasm upon treatment with an IGF1R kinase inhibitor or transduction with bone marrow cells from Igf1r+/+ mice (but not with that from Igf1r+/– mice). In samples from individuals with various types of myeloproliferative neoplasms, AIRAPL was not detected and both pro- and mature IGF1R were increased in abundance. Thus, AIRAPL limits the processing of IGF1R into its mature form in hematopoietic stem cells and thus the production of myeloid cells. These results also suggest that IGF1R inhibitors could be used in combination with existing therapies for myeloproliferative neoplasms (see LaFave and Levine). F. G. Osorio, C. Soria-Valles, O. Santiago-Fernández, T. Bernal, M. Mittelbrunn, E. Colado, F. Rodríguez, E. Bonzon-Kulichenko, J. Vázquez, M. Porta-de-la-Riva, J. Cerón, A. Fueyo, J. Li, A. R. Green, J. M. P. Freije, C. López-Otín, Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling. Nat. Med. 22, 91–96 (2016). [PubMed]L. M. LaFave, R. L. Levine, Targeting a regulator of protein homeostasis in myeloproliferative neoplasms. Nat. Med. 22, 20–21 (2016). [PubMed]

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