title: The coxsackievirus B 3C protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling.
abstract: The host innate immune response to viral infections often involves the activation of parallel pattern recognition receptor (PRR) pathways that converge on the induction of type I interferons (IFNs). Several viruses have evolved sophisticated mechanisms to attenuate antiviral host signaling by directly interfering with the activation and/or downstream signaling events associated with PRR signal propagation. Here we show that the 3C(pro) cysteine protease of coxsackievirus B3 (CVB3) cleaves the innate immune adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF) as a mechanism to escape host immunity. We found that MAVS and TRIF were cleaved in CVB3-infected cells in culture. CVB3-induced cleavage of MAVS and TRIF required the cysteine protease activity of 3C(pro), occurred at specific sites and within specialized domains of each molecule, and inhibited both the type I IFN and apoptotic signaling downstream of these adaptors. 3C(pro)-mediated MAVS cleavage occurred within its proline-rich region, led to its relocalization from the mitochondrial membrane, and ablated its downstream signaling. We further show that 3C(pro) cleaves both the N- and C-terminal domains of TRIF and localizes with TRIF to signalosome complexes within the cytoplasm. Taken together, these data show that CVB3 has evolved a mechanism to suppress host antiviral signal propagation by directly cleaving two key adaptor molecules associated with innate immune recognition.
authors: Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors: Amitava
authors: A
authors: Mukherjee
authors: Stefanie A
authors: SA
authors: Morosky
authors: Elizabeth
authors: E
authors: Delorme-Axford
authors: Naomi
authors: N
authors: Dybdahl-Sissoko
authors: M Steven
authors: MS
authors: Oberste
authors: Tianyi
authors: T
authors: Wang
authors: Carolyn B
authors: CB
authors: Coyne
mesh_terms: D000086042:3C Viral Proteases; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000502:physiology*; D029822:Enterovirus B, Human / Q000201:enzymology* / Q000276:immunology; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D007370:Interferon Type I; C505371:MAVS protein, human; C470409:TICAM1 protein, human; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases