Accumulation of lipid droplets and inflammatory cell infiltration is the hallmark of nonalcoholic steatohepatitis (NASH). The roles of noncoding RNAs in NASH are less known. We aim to elucidate the function of miR-141/200c in diet-induced NASH. WT and miR-141/200c ^–/– mice were fed a methionine and choline deficient (MCD) diet for 2 weeks to assess markers of steatosis, liver injury, and inflammation. Hepatic miR-141 and miR-200c RNA levels were highly induced in human patients with NASH fatty liver and in WT MCD mice. miR-141/200c ^–/– MCD mice had reduced liver weights and triglyceride (TG) levels, which was associated with increased microsomal TG transfer protein (MTTP) and PPARα but reduced SREBP1c and FAS expression. Inflammation was attenuated and F4/80 macrophage activation was suppressed in miR-141/200c ^–/– mice, as evidenced by decreased serum aminotransferases and IL-6 and reduced hepatic proinflammatory, neutrophil, and profibrotic genes. Treatment with LPS in BM-derived macrophages isolated from miR-200c/141 ^–/– mice polarized macrophages toward the M2 antiinflammatory state by increasing Arg1 and IL-10 levels while decreasing the M1 marker iNOS. In addition, elevated phosphorylated AMPK (p-AMPK), p-AKT, and p-GSK3β and diminished TLR4 and p-mTOR/p-4EBP1 proteins were observed. Lipidomics and metabolomics revealed alterations of TG and phosphatidylcholine (PC) lipid species by miR-141/200c deficiency. In summary, miR-141/200c deficiency diminished NASH-associated hepatic steatosis and inflammation by reprogramming lipid and inflammation signaling pathways.

Human coronaviruses (HCoVs) modify host proteins to evade the antiviral defense and sustain viral expansion. Here, we report tonicity-responsive enhancer (TonE) binding protein (TonEBP) as a cellular target of HCoVs. TonEBP was cleaved into N-terminal and C-terminal fragments (TonEBP NT and TonEBP CT, respectively) by NSP5 from all the HCoVs tested. This cleavage resulted in the loss of TonEBP’s ability to stimulate the TonE-driven transcription. On the other hand, TonEBP NT promoted viral expansion in association with the suppression of IFN-β expression. TonEBP NT competed away NF-κB binding to the PRD II domain on the IFN-β promoter. A TonEBP mutant resistant to the cleavage by NSP5 did not promote the viral expansion nor suppress the IFN-β expression. These results demonstrate that HCoVs use a common strategy of targeting TonEBP to suppress the host immune defense.

Coronaviruses rely on intricate interactions with host proteins to create an environment conducive to their replication and survival. The 3CL protease of coronavirus acts as a key mediator, serving a dual role in cleaving viral polyproteins to produce essential components for replication and targeting host proteins to disrupt regulatory pathways and suppress immune defenses. However, the mechanisms by which 3CL protease manipulates host proteins remain poorly understood. Here, we identify STIM1, a substrate of the 3CL protease, as a dual immune suppressor. Cleavage at the Q496 residue generates two stable products, N-terminal (NT) and C-terminal (CT) fragments, which acquire de novo immunomodulatory functions. NT suppresses MAVS aggregation and MAVS-TRAF2-TBK1 signalosome formation, while CT attenuates IKKα-induced p65 phosphorylation and nuclear translocation by interacting with HSP70. Collectively, these dual modules simultaneously lead to the suppression of IFN-β production and the weakening of antiviral defenses. These findings reveal a distinct function of STIM1 and delineate a strategy employed by coronaviruses to modulate host immunity, offering insights into viral pathogenesis and potential avenues for therapeutic intervention.