Dynamic bidirectional regulation of NLRC3 and gammaherpesviruses during viral latency in B lymphocytes

• Published in: Journal of medical virology Vol. 96; no. 3; pp. e29504 - n/a
• Main Authors: Kang, Hye‐Ri, Han, Ji Ho, Ng, Yee Ching, Ryu, Seungbo, Park, Ji‐Yeon, Chung, Woo‐Chang, Song, Yoon‐Jae, Chen, Szu‐Ting, Brickey, W. June, Ting, Jenny P.‐Y., Song, Moon Jung
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2024
• Subjects: Animals; B lymphocytes; EBV; Epstein-Barr virus; Epstein-Barr Virus Infections; gammaherpesvirurses; Herpesvirus 4, Human - genetics; Humans; Immune system; Infections; Intercellular Signaling Peptides and Proteins; Latency; Latent infection; Latent membrane protein 1; LMP1; Lymphocytes; Lymphocytes B; Membrane proteins; MHV‐68; Mice; NF-kappa B; NF‐κB; NLRC3; Proteasomes; Proteins; Splenocytes; Tumorigenesis; viral latency; Virus Latency; LMP1; NF-κB; viral latency; B lymphocytes; MHV-68; EBV; NLRC3; tumorigenesis; gammaherpesvirurses
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.29504

While most NOD‐like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV‐68), establish latent infection in B lymphocytes, which requires elevated NF‐κB. This study shows that during latent EBV infection of human B cells, viral‐encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1‐induced‐NF‐κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF‐κB activation by promoting the degradation of LMP1 in a proteasome‐dependent manner. In vivo, MHV‐68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3‐deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis.