We are very happy to see Akhee Sabiha Jahan's great work published in Cell Reports after years of effort! Under the supervision of Sumana Sanyal, Akhee's work illustrates the role of deubiquitylases during influenza infection and immune response.
Jahan AS, Biquand E, Muñoz-Moreno R, Le Quang A, Mok CK, Wong HH, Teo QW, Valkenburg SA, Chin AWH, Man Poon LL, Te Velthuis A, García-Sastre A, Demeret C, Sanyal S
PMID: 32023470 DOI: 10.1016/j.celrep.2020.01.015
Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [35S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses.