Repair or destruction-an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

Abstract

Cellular differentiation, developmental processes, and environmental factors challenge the integrity of the proteome in every eukaryotic cell. The maintenance of protein homeostasis, or proteostasis, involves folding and degradation of damaged proteins, and is essential for cellular function, organismal growth, and viability . Misfolded proteins that cannot be refolded by chaperone machineries are degraded by specialized proteolytic systems. A major degradation pathway regulating cellular proteostasis is the ubiquitin (Ub)/proteasome system (UPS), which regulates turnover of damaged proteins that accumulate upon stress and during aging. Despite a large number of structurally unrelated substrates, Ub conjugation is remarkably selective. Substrate selectivity is mainly provided by the group of E3 enzymes. Several observations indicate that numerous E3 Ub ligases intimately collaborate with molecular chaperones to maintain the cellular proteome. In this review, we provide an overview of specialized quality control E3 ligases playing a critical role in the degradation of damaged proteins. The process of substrate recognition and turnover, the type of chaperones they team up with, and the potential pathogeneses associated with their malfunction will be further discussed.

Keywords: CHIP; E3 ligase; aging; chaperone; proteostasis; quality control; ubiquitin.

Figure 1

Illustrative representation of subcellular localization of various PQC Ub ligases. E3 enzymes operating in quality control pathways (e.g., CHIP, Doa10, HUWE1, Listerin, Rsp5, and San1) and associated chaperones (in green and gray) are widely distributed in most subcellular compartments, including nucleus, cytoplasm, ER, and plasma membrane.

Figure 2

E3 Ub ligases with different roles in PQC. (A) CHIP is a major PQC ligase of the cytosol. (left panel) In cooperation with Hsp70/90, CHIP ameliorates proteotoxicity in various proteinopathies by referring aggregates of beta‐amyloid, mutant SOD1, polyQ protein, or alpha‐synuclein for degradation. (right panel) In addition to misfolded proteins of the cytoplasm, CHIP promotes degradation of a broad array of substrates when bound to Hsps, such as CFTR, GR, ERBB2, or HIF1A. (B) (left panel) Rsp5/Nedd4 participates in the removal of cytosolic misfolded proteins. Upon heat stress Rsp5/Nedd4 associates with cochaperone Hsp40 (Ydj1), which supports recognition and degradation of misfolded proteins. (right panel) Beyond its role in the removal of cytosolic substrates, Rsp5/Nedd4 also targets misfolded proteins at the plasma membrane. ARTs enable Rsp5 to selectively target a wide range of plasma membrane proteins and initiate their endocytosis and lysosomal degradation. (C) The E3 ligase Listerin directly associates with the 60s ribosomal subunit to specifically target newly synthesized aberrant polypeptides expressing a translated polyA tail. Listerin collaborates with three cofactors for ribosomal binding and substrate processing: NEMF, TCF25, and the Ub‐selective chaperone p97. (D) The role of chaperone‐directed E3 ligases in nuclear PQC. (left panel) San1 cooperates with Hsp70 chaperones to recruit misfolded proteins from the cytosol for proteasomal degradation in the nucleus, whereas Doa10 targets substrates independent of Hsp70/Hsp40. In addition, both Doa10 and San1 interact with Cdc48/p97 to facilitate proteasomal degradation of a subset of their substrates. (right panel) The yeast E3 ligases Hel1, Hel2, Snt2 together with the histone chaperones Pep5 and Asf1 trigger ubiquitylation and subsequent proteasomal turnover of surplus histones.