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.