An overview of the RQC pathway. (A, C) Ribosomal collisions occur when the preceding ribosome stalls during translation. In addition, stop-codon readthrough or endonucleolytic mRNA cleavage at the internally stalled ribosomes leads to 3’-end ribosome stalling. The collided ribosomes are detected by ribosome-associated collision sensors (e.g., ZNF598, EDF1). The cap-binding translation repressor complex of EIF4E2 and GIGYF2 is then recruited to the stalled ribosomes, blocking additional ribosome loading. (B, D) The RQT complex consisting of ASCC2 and ASCC3 likely senses ZNF598-dependent ubiquitination of specific ribosomal proteins (e.g., RPS10) at internally stalled ribosomes and triggers their disassembly. On the other hand, the PELO-HBS1L complex senses 3’-end ribosome stalling and recruits ABCE1 for the ribosome disassembly. (E) Nascent polypeptide chains associating with the 60S subunit undergo ubiquitindependent proteasomal degradation via three distinct pathways: 1) LTN1-dependent ubiquitination of the nascent chain for degradation (RQC-L); 2) NEMF-dependent C-terminal alanine/threonine (CAT)-tailing of the nascent chain, followed by RQC-L; and 3) NEMF-dependent alanine-tailing of the nascent chain, followed by the C-end rule pathway for protein degradation (RQC-C). Light and dark purple circles depict alanine and threonine residues, respectively, added to C-terminus of the nascent chain by NEMF activity. (F) The mRNAs are also degraded by exo- and endonucleases.

Domain architecture of PHLPP isoforms. PHLPP family retains the Ras association domain (RA), pleckstrin homology (PH) domain, leucine rich repeat region (LRR), PP2C domain and PDZ binding motif. Black arrow head denotes the splice site for PHLPP1β.