Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control.

Abstract

Protein misfolding is linked to a wide array of human diseases1,2. Protective cellular protein quality control (PQC) mechanisms evolved to selectively recognize misfolded proteins and limit their toxic effects3-9. Here we examine how molecular chaperones and the ubiquitin (Ub)-proteasome system (UPS) cooperate to recognize and promote the clearance of soluble misfolded proteins. Using a panel of PQC substrates with distinct characteristics and localization, we define distinct chaperone and ubiquitination circuitries executing quality control in the cytoplasm and nucleus. Proteasomal degradation of cytoplasmic misfolded proteins requires tagging with mixed Lysine-48 (K48) and Lysine-11 (K11) linked ubiquitin chains. A distinct combination of E3 ubiquitin ligases and specific chaperones is required to achieve each type of linkage-specific ubiquitination. Strikingly, proteasomal degradation of nuclear misfolded proteins only requires K48 linked Ub chains and is thus independent of K11 specific E3s and chaperones. The distinct Ub codes for nuclear and cytoplasmic PQC appears linked to the function of the ubiquilin Dsk2, which is specifically required for clearance of nuclear misfolded proteins. Together, our work defines the principles of cytoplasmic and nuclear PQC as distinct, involving combinatorial recognition by defined sets of cooperating chaperones and E3s. A better understanding of how these organelle-specific PQC requirements implement proteome integrity has important implications for our understanding of diseases linked to impaired protein clearance and proteostasis disfunction.