Dual cooperation between HSP70 and the 26S proteasome in co-translational protein quality control

Abstract Co-translational degradation via the ubiquitin-proteasome system mediates quality control of 15 – 25% of nascent proteins, a proportion that is known to increase dramatically as a result of proteotoxic stress. Whereas the ubiquitylation machinery involved has been characterized, mechanisms coordinating the proteasomal destruction of ribosome-attached nascent proteins remain poorly defined. In pursuit of such mechanisms, we discovered dual cooperation of the HSP70 family member HSPA1 with the 26S proteasome: First, in response to proteotoxic stress, HSPA1 promotes proteasome recruitment to translating 80S ribosomes in a manner independent of nascent chain ubiquitylation. Secondly, HSPA1, in association with its cognate nucleotide exchange factor HSPH1, maintains co-translationally ubiquitylated proteins in a soluble state required for efficient proteasomal degradation. Both mechanisms conspire to confer thermotolerance to cells and to promote the growth of esophageal cancer cells in vitro and in animals. Consistent with these observations, HSPH1 knockout impedes tumor growth in vitro and in animals and correlates with favorable prognosis in digestive tract cancers, thus nominating HSPH1 as a cancer drug target. Highlights Proteotoxic stress causes translational arrest, co-translational protein ubiquitylation, and proteasome recruitment to ribosomes Co-translational proteasome recruitment is independent of nascent chain ubiquitylation but is augmented by HSPA1 HSPA1-HSPH1 disaggregase confers thermotolerance by maintaining the solubility and proteasomal clearance of ubiquitylated proteins Low HSPH1 impedes co-translational thermotolerance and tumor growth and correlates with favorable prognosis in various cancers