Characterization of The Roles of Carma3 and Bcl10 In Virus-Triggered Rig-I/Mavs Signaling Pathway

<p>After RNA virus infection, the innate immunity utilizes RIG-I family of receptors in the cytoplasm to initiate the production of type-I IFNs and proinflammatory cytokines by mitochondrial protein MAVS, which forms a prion-like structure to recruit TBK1and IKK complex to activate IRF3 and NF-κB, respectively. Herein, we revealed the important roles of CARMA3 and BCL10 in RIG-I/MAVS signaling pathway for the first time. CARMA3 or BCL10 deficient cells exhibited partially defective NF-κB activation but hyperactivation of TBK1-IRF3 signaling pathway upon ssRNA virus infection. It led to less production of IL6 but more production of type I IFNs and resulted in CARMA3-deficient mice more resistant to virus infection, including VSV and H1N1 influenza virus. Mechanistic studies showed that CARMA3 and BCL10 physically interacted with MAVS and directly regulated MAVS aggregation. Overexpression of CARMA3 and BCL10 inhibited MAVS aggregation. Consistently, MAVS aggregation more easily occurred in CARMA3 deficient cells after VSV infection. VSV induced the cleavage of CARMA3 and led to more MAVS aggregation. These novel findings not only identified the important role of CARMA3 and BCL10 during influenza virus infection, which may provide the new target for future therapeutic interference but also revealed molecular mechanism by which CARMA3 and BCL10 orchestrated the NF-κB and IRF3 activation to balance the production of type I IFNs and proinflammatory cytokines<em>.</em></p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Zhou, Zhicheng, Mr

Contributors dc:contributor

• Dr.XinLin
• Dr.Hui-Kuan Lin
• Dr. Shao-Cong Sun

• CARMA3; BCL10; RIG-I/MAVS signaling pathway; Type I interferon; Influenza virus; VSV; Poly(I:C); DsRNA;
• Immunity
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/546

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1585