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Ubiquitin And ISG15 Conjugation At The Ribosome

Nascent polypeptides are subject to a variety of modifications while they are ribosome‐associated, including ubiquitylation and ISGylation. Ubiquitylation of nascent chains occurs on both stalled ribosomes, via the RQC/Ltn1‐dependent pathway, as well as on actively translating ribosomes in a process we refer to as co‐translational ubiquitination (CTU). CTU appears to be a conserved process in that it occurs in both yeast and human cells, and CTU is increased in both yeast and human cells in response to treatments that result in misfolding of nascent chains, such as incorporation of amino acid analogs. mTOR inhibitors (e.g., rapamycin, torin) lead to a decrease in CTU, consistent with a model where decreased translational load and/or slowing of translation may allow for increased translation fidelity and cotranslational folding efficiency. CTU products contain primarily K48‐linked polyubiquitin chains, consistent with a proteasomal targeting function. We will report on progress in identification of targets and ligases involved in CTU. Conjugation of the interferon‐induced ubiquitin‐like protein ISG15 is mediated by the Herc5 HECT domain ligase. The similarities and differences in CTU and CTI (cotranslational ISGylation) with respect to factors that influence the efficiency of each will be discussed, as well as the determinants of Herc5 that mediate ribosome association. In addition to its intracellular conjugation function, extracellular ISG15 cooperates with IL12 in the inducing the secretion of IFN‐gamma from cells within the PBMC population, particularly Natural Killer (NK) cells. We will report on progress in characterizing this unique signaling pathway.