title: Role of sHsps in organizing cytosolic protein aggregation and disaggregation.
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.
authors.affiliation: Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany. a.mogk@zmbh.uni-heidelberg.de.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. a.mogk@zmbh.uni-heidelberg.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Mogk
authors.affiliation: Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany. bukau@zmbh.uni-heidelberg.de.|German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. bukau@zmbh.uni-heidelberg.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
mesh_terms: D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D050888:Heat-Shock Proteins, Small / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D066329:Protein Aggregates; D017510:Protein Folding
chemical_list: D050888:Heat-Shock Proteins, Small; D066329:Protein Aggregates
keywords: Chaperone; Holdase, aggregase; Protein aggregation; Protein disaggregation; Small heat shock protein