Post-translational modifications of coronavirus proteins: roles and function

Fung, To Sing; Liu, Ding Xiang

Deubiquitinating activity of coronavirus PLPro Coronavirus encodes one or two PLPro in the nsp3, which carry out the proteolytic cleavage that releases nsp1, nsp2 and nsp3 from the polyprotein [15, 173, 174] . Apart from its protease activity, SARS-CoV PLPro was also shown to possess deubiquitinating (DUB) activity [175, 176] , which was also identified later for PLP2 of HCoV-NL63 [177] and MHV-A59 [178] , as well as PLPro of MERS-CoV [179, 180] and IBV [181] . Structural studies revealed that SARS-CoV PLPro shared similar fold with known DUB enzymes, but exhibited several distinct features [182] . Later studies showed that apart from ubiquitin, the PLPro of SARS-CoV and MERS-CoV also recognized another ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), and served as a deISGylating enzyme [179, 180, 183] . Interestingly, the DUB/deISGylating activity of coronavirus PLPro could be separated from its protease activity. The crystal structure of SARS-CoV PLPro in complex with human ubiquitin analog has been determined, and certain mutations in the interacting regions were shown to compromise ubiquitin binding without affecting the protease activity of PLPro [184] . Similarly, using the structure of MERS-CoV PLPro in complex with Ub as a guide, mutations were introduced into PLPro that specifically disrupted the DUB function without affecting its proteolytic activity. Unlike wild-type PLPro, the DUB lacking variants were deficient in suppressing IFN promoter activation [185] .