The Role of REC8 in the Innate Immune Response to Viral Infection

Abstract

REC8 meiotic recombination protein (REC8) is a member of structural maintenance of chromosome (SMC) protein partners, which play an important role in meiosis, anti-tumor, and sperm formation. As the adapter proteins of RLR signaling and cGAS-DNA signaling, the activity and stability of MAVS (also known as VISA, Cardif and IPS-1) and STING (also known as MITA) are critical for innate immunity. Here, we report that REC8 interacts with MAVS and STING, and inhibits their ubiquitination and subsequent degradation, thereby promoting innate antiviral signaling. REC8 is upregulated through the JAK-STAT signaling pathway under viral infection. Knockdown of REC8 impair the innate immune responses against VSV (Vesicular Stomatitis Virus), NDV (Newcastle disease virus) and HSV (herpes simplex virus). Mechanistically, under the infection of viruses, the SUMOylated REC8 is transferred from the nucleus to the cytoplasm and then interacts with MAVS and STING to inhibit their K48-linked ubiquitination triggered by RNF5. Moreover, REC8 promotes the recruitment of TBK1 to MAVS and STING. Thus, REC8 functions as a positive modulator of innate immunity. Our work highlights a previously undocumented role of meiosis-associated protein REC8 in regulating innate immunity. IMPORTANCE The innate immune response is crucial for the host to resist the invasion of viruses and other pathogens. STING and MAVS play a critical role in the innate immune response to DNA and RNA viral infection, respectively. In this study, REC8 promotes the innate immune response by targeting STING and MAVS. Notably, REC8 interacts with MAVS and STING in the cytoplasm and inhibits K48-linked ubiquitination of MAVS and STING triggered by RNF5, stabilizing MAVS and STING protein to promote innate immunity and gradually inhibiting viral infection. Our study provides a new insight for the study of antiviral innate immune.

Transcriptomic profiling implicates PAF1 in both active and repressive immune regulatory networks

“…S4A). Interestingly, REC8 promotes innate immune signaling via stabilization of MAVS and STING [50], connecting back to our previously identified dysregulation of the cGAS-STING pathway (Fig. 2B).…”

Establishment of a CRISPR/Cas9 knockout library for screening type I interferon-inducible antiviral effectors in pig cells

“…Besides, a loss-of-function screen using a small interfering RNA (siRNA) library identified IRF9 as the most significantly enriched hit responsible for the activity of IFN-a against VSV, Indiana serotype (VSV IND ) (30). (II) IFITM1/IFITM3 restricted VSV replication potentially through toughening the host membrane, thus preventing viral membrane fusion (19); (III) REC8 promoted the innate immune response by targeting STING and MAVS, thus constraining VSV replication (20). Noticeable is the fact that those four hits are on the top of list.…”

ClpP-Deletion Causes Azoospermia, with Meiosis-I Delay and Insufficient Biosynthesis of Spermatid Factors, Due to Mitochondrial Dysfunction with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2

“…Although the azoospermia of ClpP-null mice was not mitigated when downstream immune signals were blocked by genetic deletion of STING and IFNAR, it is possible that mtDNA pathology impacts meiosis further upstream in the antiviral program. One example is the sequestration of nuclear REC8 to the mitochondrial outer membrane in association with the MAVS protein upon virus exposure [91], but there are presumably other unknown direct interactions that do not depend on type I interferon production.…”

“…Although the SC axial element component Rec8 was previously reported to be also induced by retinoic acid [57], a paradoxical transcriptional downregulation of Rec8 at P27 was observed, and this significant reduction at mRNA and protein level was the first molecular block during ClpP-null spermatogensis observed in the current profiling effort. It is interesting to note that REC8 is regulated by proteolytic cleavage via the downregulated separin, is protected in its centromere association by SGOL2, and is relocalized to associate with mitochondrial surface MAVS during antiviral responses [25,58,59]. Thus, REC8 is a key molecule connecting mitochondrial pathology and proteostasis with meiosis.…”