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The integrated stress response, especially stress granules (SGs), contributes to host immunity. Typical G3BP1+ stress granules (tSGs) are usually formed after virus infection to restrain viral replication and stimulate innate immunity. Recently, several SG-like foci or atypical SGs (aSGs) with proviral function have been found during viral infection. We have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein induces atypical N+/G3BP1+ foci (N+foci), leading to the inhibition of host immunity and facilitation of viral infection. However, the precise mechanism has not been well clarified yet. In this study, we showed that the SARS-CoV-2 N (SARS2-N) protein inhibits dsRNA-induced growth arrest and DNA damage-inducible 34 (GADD34) expression. Mechanistically, the SARS2-N protein promotes the interaction between GADD34 mRNA and G3BP1, sequestering GADD34 mRNA into the N+foci. Importantly, we found that GADD34 participates in IRF3 nuclear translocation through its KVRF motif and promotes the transcription of downstream interferon genes. The suppression of GADD34 expression by the SARS2-N protein impairs the nuclear localization of IRF3 and compromises the host’s innate immune response, which facilitates viral replication. Taking these findings together, our study revealed a novel mechanism by which the SARS2-N protein antagonized the GADD34-mediated innate immune pathway via induction of N+foci. We think this is a critical strategy for viral pathogenesis and has potential therapeutic implications.

A total of 26 mice were observed with vaginal septa and 10 of them progressively developed into vaginal atresia. Among these vaginal atresia mice, 6 mice eventually suffered from uterus hydrometrocolpos syndrome (HMCPS) and polycystic ovary syndrome (PCOS) and the others were cured with surgical intervention once the vaginal orifices were found closed. Imaging and pathological observation showed that vaginal atresia led to cervix's lipoid secretion and uterine effusion. Moreover, Serum biochemical examination and ELISA test revealed significantly dramatic drop (about 50%) in blood triglycerides (P<0.01) and double increase in aromatase (P<0.01) in vaginal atresia mice. These findings give gained variable insight into further studies and provide vital guide for therapy on vaginal atresia. [ABSTRACT FROM AUTHOR]