Mechanistic studies of the ribosome-associated quality control pathway

Abstract

Ribosomes translating faulty mRNA can stall and collide, triggering non-canonical splitting. The split large subunit retains peptidyl tRNA and is resolved by the ribosome-associated quality control (RQC) pathway. During RQC, stalled polypeptides at split large subunits can be extended with C-terminal alanine/threonine (CAT) tails prior to proteasomal degradation. If undegraded, CAT tails drive stalled polypeptide aggregation. My first project investigated the mechanism of this aggregation process. Through investigating the aggregation profiles of C-terminal tails of varying compositions, I discovered that threonine-rich tails initiate aggregation, forming seeds that recruit other proteins to drive aggregate growth. My second project explored the possibility of an alternative RQC activation mechanism. Evidence was provided for a novel RQC activation route independent of faulty mRNA and upstream ribosome splitting factors. Together, these two projects offer novel insights into RQC mechanisms, furthering our understanding of this highly conserved protein surveillance pathway.