Mechanisms of Protein Quality Control in the Endoplasmic Reticulum by a Coordinated Hsp40-Hsp70-Hsp90 System

The Hsp40, Hsp70, and Hsp90 chaperone families are ancient, highly conserved, and critical to cellular protein homeostasis. Hsp40 chaperones can transfer their protein clients to Hsp70, and Hsp70 can transfer clients to Hsp90, but the functional benefits of these transfers are unclear. Recent structural and mechanistic work has opened up the possibility of uncovering how Hsp40, Hsp70, and Hsp90 work together as unified system. In this review, we compile mechanistic data on the ER J-domain protein 3 (ERdj3) (an Hsp40), BiP (an Hsp70), and Grp94 (an Hsp90) chaperones within the endoplasmic reticulum; what is known about how these chaperones work together; and gaps in this understanding. Using calculations, we examine how client transfer could impact the solubilization of aggregates, the folding of soluble proteins, and the triage decisions by which proteins are targeted for degradation. The proposed roles of client transfer among Hsp40-Hsp70-Hsp90 chaperones are new hypotheses, and we discuss potential experimental tests of these ideas.