Role of sHsps in organizing cytosolic protein aggregation and disaggregation - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jul;22(4):493-502.
doi: 10.1007/s12192-017-0762-4. Epub 2017 Jan 24.

Role of sHsps in organizing cytosolic protein aggregation and disaggregation

Axel Mogk  1   2 , Bernd Bukau  3   4
Affiliations
Review

Role of sHsps in organizing cytosolic protein aggregation and disaggregation

Axel Mogk et al. Cell Stress Chaperones. 2017 Jul.

Abstract

Small heat shock proteins (sHsps) exhibit an ATP-independent chaperone activity to prevent the aggregation of misfolded proteins in vitro. The seemingly conflicting presence of sHsps in insoluble protein aggregates in cells obstructs a precise definition of sHsp function in proteostasis networks. Recent findings specify sHsp activities in protein quality control systems. The sHsps of yeast, Hsp42 and Hsp26, interact with early unfolding intermediates of substrates, keeping them in a ready-to-refold conformation close to the native state. This activity facilitates substrate refolding by ATP-dependent Hsp70-Hsp100 disaggregating chaperones. Hsp42 can actively sequester misfolded proteins and promote their deposition at specific cellular sites. This aggregase activity represents a cytoprotective protein quality control strategy. The aggregase function of Hsp42 controls the formation of cytosolic aggregates (CytoQs) under diverse stress regimes and can be reconstituted in vitro, demonstrating that Hsp42 is necessary and sufficient to promote protein aggregation. Substrates sequestered at CytoQs can be dissociated by Hsp70-Hsp100 disaggregases for subsequent triage between refolding and degradation pathways or are targeted for destruction by selective autophagy termed proteophagy.

Keywords: Chaperone; Holdase, aggregase; Protein aggregation; Protein disaggregation; Small heat shock protein.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
The yeast sHsps, Hsp26 and Hsp42, sequester substrates in near-native states. Without sHsps, substrates globally unfold and form tight protein aggregates. In presence of sHsps (Hsp26, Hsp42), early unfolding intermediates of substrates are sequestered within sHsp/substrate complexes. The sHsps preserve a native-like core structure of bound substrates and increase the distance between non-native protein molecules keeping substrates separated. These features contribute to facilitated substrate refolding by disaggregating Hsp70-Hsp100 chaperones
Fig. 2
Fig. 2
Destiny of substrates sequestered at CytoQs in an Hsp42-dependent process. a Formation of cytosolic aggregates (CytoQs) under physiological heat stress (38 °C) requires Hsp42, which promotes protein aggregation and mediates aggregate coalescence. Substrates deposited at CytoQs are rescued by the Hsp70-Hsp100 disaggregase system. Solubilized substrates are either refolded or degraded by the ubiquitin-proteasome system (UPS). b Dysfunctional, ubiquitinated 26S proteasomes are sequestered in an Hsp42-dependent manner. CytoQs including dysfunctional 26S proteasome subunits are potentially transported and anchored to the vacuole in a Myo2- and Vac17-dependent process. The adaptor protein Cue5 links the sequestered proteasomal subunits to the Atg8 receptor at the phagophore. This results in the formation of autophagosomes and the engulfment of CytoQs, which are finally degraded by vacuolar peptidases
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science. 2003;299:1751–1753. doi: 10.1126/science.1080418. - DOI - PubMed
    1. Alberti S, Halfmann R, King O, Kapila A, Lindquist S. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell. 2009;137:146–158. doi: 10.1016/j.cell.2009.02.044. - DOI - PMC - PubMed
    1. Allen SP, Polazzi JO, Gierse JK, Easton AM. Two novel heat shock genes encoding proteins produced in response to heterologous protein expression in Escherichia coli. J Bacteriol. 1992;174:6938–6947. doi: 10.1128/jb.174.21.6938-6947.1992. - DOI - PMC - PubMed
    1. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004;431:805–810. doi: 10.1038/nature02998. - DOI - PubMed
    1. Arrigo AP, Suhan JP, Welch WJ. Dynamic changes in the structure and intracellular locale of the mammalian low-molecular-weight heat shock protein. Mol Cell Biol. 1988;8:5059–5071. doi: 10.1128/MCB.8.12.5059. - DOI - PMC - PubMed

Publication types

Substances

LinkOut - more resources