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Cancer stem cells (CSCs) are responsible for tumor chemoresistance, and the aryl hydrocarbon receptor (AHR) is indispensable for maintaining CSC characteristics. Here, we aimed to investigate how the interaction between progesterone receptor membrane component 1 (PGRMC1) and AHR contributes to the maintenance of CSC phenotypes in non-small cell lung cancer (NSCLC). Clinical data and tissue microarray analyses indicated that patients with elevated PGRMC1 expression had poorer prognoses. Moreover, PGRMC1 overexpression enhanced CSC phenotypes and chemotherapy resistance in vitro and in vivo by modulating AHR ubiquitination. We then determined the specific interaction sites between PGRMC1 and AHR. Mass spectrometry screening identified tripartite motif containing 56 (TRIM56) as the E3 ligase targeting AHR. Notably, PGRMC1 overexpression inhibited the interaction between TRIM56 and AHR. Overall, our study revealed a regulatory mechanism that involves PGRMC1, AHR, and TRIM56, providing insights for developing CSC-targeting strategies in NSCLC treatment. • PGRMC1 promotes stemness phenotypes in NSCLC, leading to poor prognosis. • PGRMC1 interacts with AHR and enhances cancer stem cell markers ABCG2, ALDH1A1 and CD44 via the AHR pathway. • PGRMC1 maintains AHR protein levels by inhibiting its ubiquitination. • TRIM56 is a specific E3 ubiquitin ligase for AHR. • PGRMC1 overexpression inhibits TRIM56 and AHR interaction. [ABSTRACT FROM AUTHOR]

Nuclear factor-κB (NF-κB) signaling participates in many biologic processes including immunity, inflammation, and cancer. Here we reported that tripartite motif-containing protein 56 (TRIM56), an E3 ligase enzyme, participated in TNFα-induced NF-κB signaling by interacting with TAK1. Overexpression of TRIM56 potentiated the activation of TNFα-induced NF-κB signaling, whereas knockdown of TRIM56 had an opposite effect. TRIM56 enhanced the ubiquitination of TAK1, specifically enhanced the M1-linked polyubiquitin chains to TAK1, leading to the tight interactions of the TAK1-IKKα complex. Consequently, the stimulation of TNFa and TRIM56 strengthened the interaction with TAK1. Furthermore, we found that the C terminal (CT) domain was the binding region of TRIM56, and the RING domain of TRIM56 was the E3 enzyme activity region which was important to the ubiquitination of TAK1. Together, these results reveal that TRIM56 positively regulates TNFα-induced NF-κB signaling by heightening the ubiquitination of TAK1 and provide new insight into the complicated mechanisms of the inflammatory and immune response. [ABSTRACT FROM AUTHOR]

Members of the tripartite motif (TRIM) protein family strongly induced by interferons (IFNs) are parts of the innate immune system with antiviral activity. However, it is still unclear which TRIMs could play important roles in hepatitis B virus (HBV) inhibition. Here, we identified that TRIM56 expression responded in IFN-treated HepG2-NTCP cells and HBV-infected liver tissues, which was a potent IFN-inducible inhibitor of HBV replication. Mechanistically, TRIM56 suppressed HBV replication via its Ring and C-terminal domain. C-terminal domain was essential for TRIM56 translocating from cytoplasm to nucleus during HBV infection. Further analysis revealed that TRIM56's Ring domain targeted IκBα for ubiquitination. This modification induced phosphorylation of p65, which subsequently inhibited HBV core promoter activity, resulting in the inhibition of HBV replication. The p65 was found to be necessary for NF-κB signal pathway to inhibit HBV replication. We verified our findings using HepG2-NTCP and primary human hepatocytes. Our findings reveal that TRIM56 is a critical antiviral immune effector and exerts an anti-HBV activity via NF-κB signal pathway, which is essential for inhibiting transcription of HBV covalently closed circular DNA. [Display omitted] • TRIM56 inhibits infection and replication of HBV. • TRIM56 restricts HBV core promoter activity. • TRIM56 Ring domain ubiquitinates IκBα to active NF-КB pathway. • TRIM56 inhibit HBV replication through phosphorylated p65 to suppress HBV transcription. [ABSTRACT FROM AUTHOR]

During embryogenesis, neural stem/progenitor cells (NPCs) proliferate and differentiate to form brain tissues. Here, we show that in the developing murine cerebral cortex, the balance between the NPC maintenance and differentiation is coordinated by ubiquitin signals that control the formation of processing bodies (P-bodies), cytoplasmic membraneless organelles critical for cell state regulation. We find that the deubiquitinase Otud4 and the E3 ligase Trim56 counter-regulate the ubiquitination status of a core P-body protein 4E-T to orchestrate the assembly of P-bodies in NPCs. Aberrant induction of 4E-T ubiquitination promotes P-body assembly in NPCs and causes a delay in their cell cycle progression and differentiation. In contrast, loss of 4E-T ubiquitination abrogates P-bodies and results in premature neurogenesis. Thus, our results reveal a critical role of ubiquitin-dependent regulation of P-body formation in NPC maintenance and neurogenesis during brain development. [Display omitted] • The deubiquitinase Otud4 regulates neural progenitor self-renewal and neurogenesis • Dynamic 4E-T ubiquitination coordinates neural progenitor homeostasis • 4E-T ubiquitination induces the recruitment of P-body components for assembly • Otud4 and Trim56 counter-regulate 4E-T ubiquitination to control progenitor homeostasis Kedia et al. show that dynamic ubiquitination of the P-body protein 4E-T controls P-body formation in neural stem/progenitor cells (NPCs). The deubiquitinase Otud4 and the E3 ligase Trim56 counter-regulate 4E-T ubiquitination to coordinate NPC maintenance and differentiation in the developing murine cerebral cortex. [ABSTRACT FROM AUTHOR]