[대학원 생명과학과 세미나 안내]
연사 : 신동혁 교수(연세대학교, 생명시스템대학 시스템생물학과)
연제 : Ubiquitin arms race between pathogens and hosts: deubiquitinases from Legionella and SARS-CoV-2
일시 : 2021년 03월 19일 (금) 오후 5시
장소 : 온라인 화상 강의로 진행됩니다.
초청교수 : 송현규 교수
Abstract
Pathogenic bacteria or viruses alter the host-ubiquitination system, which is critical for the host defense mechanisms upon infection. Among them, Legionella pneumophilia, an intracellular pathogenic bacterium, injects SidE family effectors into the host cells. SidE family has been implicated in unconventional phosphoribosyl-linked serine ubiquitination (PR-ubiquitination). Unlike the conventional ubiquitination, the SidE family catalyzes NAD+ and does not require E1, E2, E3 enzyme cascades. Legionella also have two genes encoding DeUbiquitinase for Phosphoribosyl-ubiquitination (DUPs, DupA/B) that specifically cleave PR-ubiquitin from serine residues on host substrates. I will summarize the recent discoveries on PR-ubiquitination and provide the fundamental basis of this novel ubiquitination system.
Next, I would like to introduce another deubiquitinase, papain-like protease (PLpro) from SARS-CoV-2. PLpro is not only required for polyprotein processing during viral maturation but also for cleavage of ubiquitin or ISG15 from host proteins. We provided biochemical, structural, and functional characterizations of PLpro from SARS-CoV-2 (PLproCoV2) and revealed differences to that of SARS (PLproSARS). PLproCoV2 predominantly cleaves ISG15 off from host proteins, while PLproSARS preferentially targets ubiquitin chains. The crystal structure of PLproCoV2 in complex with ISG15 explains the higher specificity through distinctive interactions to ISG15’s amino-terminal ubiquitin-like domain. We also suggested GRL-0617 as a non-covalent inhibitor of PLpro, which was further verified and found to rely on conserved PLproCoV2 Tyr268. We also showed that PLproCoV2 cleaves ISG15 from interferon responsive factor 3 (IRF3), blocks its nuclear translocation, and reduces type I interferon responses. Inhibition of PLproCoV2 by GRL-0617 blocks the virus-induced cytopathogenic effect upon infection with SARS-CoV-2, reduces viral release from infected cells, and fosters the anti-viral interferon pathway. We propose that therapeutic targeting of PLproCoV2 can inhibit SARS-CoV-2 infection and promote anti-viral immunity.