Hsp70 at the membrane: driving protein translocation

Craig, Elizabeth A.

doi:10.1186/s12915-017-0474-3

Cited by 145 publications

(129 citation statements)

References 94 publications

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“…Chaperones are highly conserved molecular machines that control cellular protein homeostasis (proteostasis). Across species, they promote de novo protein folding and protein maturation (1), protein translocation (2), protein-complexes assembly and disassembly (3), protein disaggregation and refolding (4), and protein degradation (5).…”

Section: Introductionmentioning

confidence: 99%

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

Shemesh

Jubran

Abu-Qarn

et al. 2020

Preprint

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The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Here, we used human tissue RNAsequencing profiles to analyze the expression and organization of chaperones across 29 main tissues. We found that relative to protein-coding genes, chaperones were significantly more ubiquitously and highly expressed across all tissues. Nevertheless, differential expression analysis revealed that most chaperones were up-or downregulated in certain tissues, suggesting that they have tissue-specific roles. In agreement, chaperones that were upregulated in skeletal muscle were highly enriched in mouse myoblasts and in nematode's muscle tissue, and overlapped significantly with chaperones that are causal for muscle diseases. We also identified a distinct subset of chaperones that formed a uniformly-expressed, cross-family core group conducting basic cellular functions that was significantly more essential for cell survival. Altogether, this suggests a layered architecture of chaperones across tissues that is composed of shared core elements that are complemented by variable elements which give rise to tissue-specific functions and sensitivities, thereby contributing to the tissue-specificity of protein misfolding diseases. Significance StatementProtein misfolding diseases, such as neurodegenerative disorders and myopathies, are often manifested in a specific tissue or even a specific cell type. Enigmatically, however, they are typically caused by mutations in widely expressed proteins. Here we focused on chaperones, the main and basic components of the protein-folding machinery of cells. Computational analyses of large scale tissue transcriptomes unveils that the chaperone system is composed of core essential elements that are uniformly expressed across tissues, and of variable elements that are differentially expressed in a tissue-specific manner. This organization allows each tissue to fit the quality control system to its specific requirements and illuminates the mechanisms that underlie a tissue's susceptibility to protein-misfolding diseases.

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Section: Introductionmentioning

confidence: 99%

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

Shemesh

Jubran

Abu-Qarn

et al. 2020

Preprint

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“…Although the SRP-dependent insertion of protein into the ER membrane (Fig. 4, left and middle) is generally thought to be the dominant process, the SRP-independent insertion has also been described (73,74). In yeast, nascent polypeptides with signal sequences not recognized efficiently by SRP are bound by soluble chaperone Ssa1, targeting the nascent chains to the Sec63 complex (Fig.…”

Section: Srp-independent Er Insertionmentioning

confidence: 99%

Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

Lee

Zhao

2019

Journal of Biological Chemistry

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Edited by Mike Shipston Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structurally distinct messengers that mobilize the endoplasmic and endolysosomal Ca 2؉ stores, respectively. Both are synthesized by the CD38 molecule (CD38), which has long been thought to be a type II membrane protein whose catalytic domain, intriguingly, faces to the outside of the cell. Accordingly, for more than 20 years, it has remained unresolved how CD38 can use cytosolic substrates such as NAD and NADP to produce messengers that target intracellular Ca 2؉ stores. The discovery of type III CD38, whose catalytic domain faces the cytosol, has now begun to clarify this topological conundrum. This article reviews the ideas and clues leading to the discovery of the type III CD38; highlights an innovative approach for uncovering its natural existence; and discusses the regulators of its activity, folding, and degradation. We also review the compartmentalization of cADPR and NAADP biogenesis. We further discuss the possible mechanisms that promote type III CD38 expression and appraise a proposal of a Ca 2؉-signaling mechanism based on substrate limitation and product translocation. The surprising finding of another enzyme that produces cADPR and NAADP, sterile ␣ and TIR motif-containing 1 (SARM1), is described. SARM1 regulates axonal degeneration and has no sequence similarity with CD38 but can catalyze the same set of multireactions and has the same cytosolic orientation as the type III CD38. The intriguing finding that SARM1 is activated by nicotinamide mononucleotide to produce cADPR and NAADP suggests that it may function as a regulated Ca 2؉-signaling enzyme like CD38.

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“…The substratebinding pocket is closed on ATP hydrolysis and release of ADP results in substrate release. In addition to refolding soluble proteins, Hsp70 supports protein import into cellular compartments such as the endoplasmic reticulum and mitochondria, where the proteins have to pass membranes in an unfolded state, through an import channel (Craig, 2018). Moreover, Hsp70 support protein degradation machineries requiring soluble and at least partially unfolded proteins, like the 26S proteasome (Fernández-Fernández et al, 2017).…”

Section: Hsp70 Chaperonesmentioning

confidence: 99%

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

Escobar-Henriques¹,

Altin²,

Brave³

2020

Current Issues in Molecular Biology

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Eukaryotic cells are subdivided into membranebound compartments specialized in different cellular functions and requiring dedicated sets of proteins. Although cells developed compartmentspecific mechanisms for protein quality control, chaperones and ubiquitin are generally required for maintaining cellular proteostasis. Proteotoxic stress is signalled from one compartment into another to adjust the cellular stress response. Moreover, transport of misfolded proteins between different compartments can buffer local defects in protein quality control. Mitochondria are special organelles in that they possess an own expression, folding and proteolytic machinery, of bacterial origin, which do not have ubiquitin. Nevertheless, the importance of extensive crosstalk between mitochondria and other subcellular compartments is increasingly clear. Here, we will present local quality control mechanisms and discuss how cellular proteostasis is affected by the interplay between mitochondria and the ubiquitin proteasome system.

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Hsp70 at the membrane: driving protein translocation

Cited by 145 publications

References 94 publications

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

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