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N4BP3 Regulates RIG-I-Like Receptor Antiviral Signaling Positively by Targeting Mitochondrial Antiviral Signaling Protein.

ABSTRACT: Mitochondrial antiviral signaling protein (MAVS), an adaptor protein, is activated by RIG-I, which is critical for an effective innate immune response to infection by various RNA viruses. Viral infection causes the RIG-I-like receptor (RLR) to recognize pathogen-derived dsRNA and then becomes activated to promote prion-like aggregation and activation of MAVS. Subsequently, through the recruitment of TRAF proteins, MAVS activates two signaling pathways mediated by TBK1-IRF3 and IKK- NF-κb, respectively, and turns on type I interferon and proinflammatory cytokines. This study discovered that NEDD4 binding protein 3 (N4BP3) is a positive regulator of the RLR signaling pathway by targeting MAVS. Overexpression of N4BP3 promoted virus-induced activation of the interferon-β (IFN-β) promoter and interferon-stimulated response element (ISRE). Further experiments showed that knockdown or knockout N4BP3 impaired RIG-I-like receptor (RLR)-mediated innate immune response, induction of downstream antiviral genes, and cellular antiviral responses. We also detected that N4BP3 could accelerate the interaction between MAVS and TRAF2. Related experiments revealed that N4BP3 could facilitate the ubiquitination modification of MAVS. These findings suggest that N4BP3 is a critical component of the RIG-I-like receptor (RLR)-mediated innate immune response by targeting MAVS, which also provided insight into the mechanisms of innate antiviral responses.

SUBMITTER: Wang C

PROVIDER: S-EPMC8646042 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Myeloid cells are critical cells involved in the orchestration of innate and adaptive immune responses. Most myeloid cells derive from the adult bone marrow in a process called myelopoiesis, a tightly controlled process that ensures constant production of myeloid cells. Sex differences in myeloid cell development have been observed; males exhibit greater monocytic differentiation in the bone marrow, and men have increased blood monocyte numbers when compared to women. Here we use a genetic mouse model of myeloid androgen receptor (AR) knockout (MARKO) and pharmacological inhibition of AR to investigate the role of androgen signaling in monocytic differentiation. We observe that although myeloid AR signaling does not influence total bone marrow cell numbers, it does affect the composition of the bone marrow myeloid population in both homeostatic and emergency settings. Genetic deletion of AR in myeloid cells led to reduced monocytic development in vivo. Similarly, pharmacologic inhibition of AR signaling in vitro reduced monocytic development. However, alteration in monocytic differentiation in the absence of AR signaling did not lead to reduced numbers of circulating myeloid cells, although MARKO male mice display reduced ratio of classical to non-classical monocytes in the blood, implying that blood monocyte subsets are skewed upon myeloid AR deletion. Our results suggest that the sex differences observed in monocytic differentiation are partly attributed to the positive role of the androgen-AR axis in regulating monocytic development directly at the myeloid cell level. Furthermore, we have identified a novel role for AR in regulating blood mature monocyte subset turnover. Investigating how androgen signaling affects monocytic development and monocyte subset heterogeneity will advance our understanding of sex differences in monocytic function at homeostasis and disease and can ultimately impact future therapeutic design targeting monocytes in the clinic.

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N4BP3 Regulates RIG-I-Like Receptor Antiviral Signaling Positively by Targeting Mitochondrial Antiviral Signaling Protein.

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