Boran Chang

Abstract Internal N 6 -methyladenosine (m 6 A) modifications are among the most abundant modifications of messenger RNA, playing a critical role in diverse biological and pathological processes. However, the functional role and regulatory mechanism of m 6 A modifications in the immune response to Mycobacterium tuberculosis infection remains unknown. Here, we report that methyltransferase-like 14 (METTL14)-dependent m 6 A methylation of NAPDH oxidase 2 ( Nox2 ) mRNA was crucial for the host immune defense against M. tuberculosis infection and that M. tuberculosis -secreted antigen EsxB (Rv3874) inhibited METTL14-dependent m 6 A methylation of Nox2 mRNA. Mechanistically, EsxB interacted with p38 MAP kinase and disrupted the association of TAB1 with p38, thus inhibiting the TAB1-mediated autophosphorylation of p38. Interaction of EsxB with p38 also impeded the binding of p38 with METTL14, thereby inhibiting the p38-mediated phosphorylation of METTL14 at Thr72. Inhibition of p38 by EsxB restrained liquid–liquid phase separation (LLPS) of METTL14 and its subsequent interaction with METTL3, preventing the m 6 A modification of Nox2 mRNA and its association with the m 6 A-binding protein IGF2BP1 to destabilize Nox2 mRNA, reduce ROS levels, and increase intracellular survival of M. tuberculosis . Moreover, deletion or mutation of the phosphorylation site on METTL14 impaired the inhibition of ROS level by EsxB and increased bacterial burden or histological damage in the lungs during infection in mice. These findings identify a previously unknown mechanism that M. tuberculosis employs to suppress host immunity, providing insights that may empower the development of effective immunomodulators that target M. tuberculosis .

ABSTRACT Obesity remains a severe global public health challenge, with contemporary therapeutic approaches primarily focusing on appetite suppression. Here, we discovered HLY72, a lycorine-derived small molecule that potently counteracts obesity in mice at doses without affecting food intake, by promoting sympathetic activation-mediated lipolysis and thermogenesis in adipose tissues. Mass spectrometry identified Na + /K + -ATPase (NKA) α3, the brain-specific isoform, as HLY72’s target. Only blood-brain barrier-permeable NKA inhibitors reproduce HLY72’s anti-obesity effects, and resistance to HLY72 treatment occurs specifically in NKA α3 (not α1) knockin mice harboring a HLY72-binding mutation. Similar to the chemical inhibition by HLY72, genetic inhibition of NKA α3 also effectively protects mice from diet-induced obesity. These findings point NKA α3 as a potent anti-obesity drug target and highlight HLY72’s potential in treating and preventing obesity independent of appetite control.