MAVS is essential for antiviral immunity, but the molecular mechanisms responsible for its tight regulation remain poorly understood. Here, we show that NLK inhibits the antiviral immune response during viral infection by targeting MAVS for degradation. NLK depletion promotes virus-induced antiviral cytokine production and decreases viral replication, which is potently rescued by the reintroduction of NLK. Moreover, the depletion of NLK promotes antiviral effects and increases the survival times of mice after infection with VSV. NLK interacts with and phosphorylates MAVS at multiple sites on mitochondria or peroxisomes, thereby inducing the degradation of MAVS and subsequent inactivation of IRF3. Most importantly, a peptide derived from MAVS promotes viral-induced IFN-β production and antagonizes viral replication in vitro and in vivo. These findings provide direct insights into the molecular mechanisms by which phosphorylation of MAVS regulates its degradation and influences its activation and identify an important peptide target for propagating antiviral responses.

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Serum response factor (SRF) regulates differentiation and proliferation by binding to RhoA-actin-activated MKL or Ras-MAPK-activated ELK transcriptional coactivators, but the molecular mechanisms responsible for SRF regulation remain unclear. Here, we show that Nemo-like kinase (NLK) is required for the promotion of SRF/ELK signaling in human and mouse cells. NLK was found to interact with and phosphorylate SRF at serine residues 101/103, which in turn enhanced the association between SRF and ELK. The enhanced affinity of SRF/ELK antagonized the SRF/MKL pathway and inhibited mouse myoblast differentiation in vitro. In a skeletal muscle-specific Nlk conditional knockout mouse model, forming muscle myofibers underwent hypertrophic growth, resulting in an increased muscle and body mass phenotype. We propose that both phosphorylation of SRF by NLK and phosphorylation of ELKs by MAPK are required for RAS/ELK signaling, confirming the importance of this ancient pathway and identifying an important role for NLK in modulating muscle development in vivo.

The catenin beta 1 gene (CTNNB1) plays a crucial role in the malignant progression of various cancers. Emerging studies have suggested that its hyperactivation is closely related to the occurrence and development of bladder cancer(BCa). Here, we report that UCHL3(Ubiquitin C-terminal hydrolase L3), a deubiquitinating enzyme promotes the development of bladder cancer through Wnt signaling pathway by interacting with and stabilizing CTNNB1 in vitro and in vivo. GSEA analysis showed that UCHL3 was highly associated with Wnt signaling pathway, and it was validated by luciferase reporter assays and RT-PCR, which found that its functions depend on its deubiquitinating activity. We also found that the overexpression of UCHL3 boosted the bladder cancer cells proliferation, invasion and migration, while the depletion of UCHL3 in bladder cancer cells delayed the tumor tumorigenesis in vitro and in vivo. Especially, Uchl3-deficient mice were less susceptible to bladder tumorigenesis. Additionally, UCHL3 was highly expressed in bladder cancer and associated with advanced clinicopathological parameters. These findings provided direct insight into the molecular mechanism of the functions of UCHL3 in bladder cancer, and provided new target for therapeutic approach against bladder cancer.