The Extent of Ssa1/Ssa2 Hsp70 Chaperone Involvement in Nuclear Protein Quality Control Degradation Varies With the Substrate

Ramon D. Jones, University of Washington
Charisma Enam, University of Washington
Rebeca Ibarra, University of Nevada, Las Vegas
Heather R. Borror, University of Washington
Kaitlyn E. Mostoller, University of Washington
Eric K. Fredrickson, University of Washington
JiaBei Lin, University of Pennsylvania
Edward Chuang, University of Pennsylvania
Zachary March, University of Pennsylvania
James Shorter, University of Pennsylvania
Tommer Ravid, The Hebrew University of Jerusalem, Givat-Ram
Gary Kleiger, University of Nevada, Las Vegas
Richard G. Gardner, University of Washington


Protein misfolding is a recurring phenomenon that cells must manage; otherwise misfolded proteins can aggregate and become toxic should they persist. To counter this burden, cells have evolved protein quality control (PQC) mechanisms that manage misfolded proteins. Two classes of systems that function in PQC are chaperones that aid in protein folding and ubiquitin–protein ligases that ubiquitinate misfolded proteins for proteasomal degradation. How folding and degradative PQC systems interact and coordinate their respective functions is not yet fully understood. Previous studies of PQC degradation pathways in the endoplasmic reticulum and cytosol have led to the prevailing idea that these pathways require the activity of Hsp70 chaperones. Here, we find that involvement of the budding yeast Hsp70 chaperones Ssa1 and Ssa2 in nuclear PQC degradation varies with the substrate. In particular, nuclear PQC degradation mediated by the yeast ubiquitin–protein ligase San1 often involves Ssa1/Ssa2, but San1 substrate recognition and ubiquitination can proceed without these Hsp70 chaperone functions in vivo and in vitro. Our studies provide new insights into the variability of Hsp70 chaperone involvement with a nuclear PQC degradation pathway.