Tissue & cell · 2026
METTL14/YTHDF1 axis restores ULK1-mediated autophagic flux to suppress Mycobacterium tuberculosis survival.
СтатьяНазвание и аннотация: Перевод в очереди
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Gao Mingjian, Cao Shipeng, Liu Huimin
Аннотация
BACKGROUND: Tuberculosis (TB) continues to be a major global infectious disease, and the ability of Mycobacterium tuberculosis (Mtb) to persist within macrophages is a major barrier to eradication. Autophagy is a critical host defense mechanism, yet the epitranscriptomic regulation of this process is poorly understood.
METHODS: PBMCs isolated from individuals with TB and THP-1 macrophages infected with Mtb H37Ra were analyzed for METTL14 expression. Functional modulation experiments were conducted to investigate autophagy, m6A modification, and bacterial survival. Techniques included qPCR, Western blot, immunofluorescence, Me-RIP, RIP, dual-luciferase reporter assays, RNA stability analysis, and CFU enumeration.
RESULTS: METTL14 level was significantly decreased in PBMCs of TB patients and in Mtb-infected macrophages. Overexpression of METTL14 restored autophagic flux, as evidenced by increased LC3 puncta, elevated Beclin-1 and ULK1 levels, and enhanced p62 degradation. Mechanistically, METTL14 mediated m6A modification of ULK1 mRNA, which was recognized by YTHDF1 to stabilize the transcript. Silencing ULK1 abrogated METTL14-induced autophagic flux, while pharmacological inhibition of autophagy reversed the suppression of intracellular Mtb survival by METTL14.
CONCLUSION: These findings identify METTL14 as a key epitranscriptomic regulator of autophagic flux in macrophages during Mtb infection. By promoting m6A modification and stabilization of ULK1 mRNA, METTL14 restores autophagic flux and restricts bacterial persistence, highlighting a potential therapeutic target for TB.
METHODS: PBMCs isolated from individuals with TB and THP-1 macrophages infected with Mtb H37Ra were analyzed for METTL14 expression. Functional modulation experiments were conducted to investigate autophagy, m6A modification, and bacterial survival. Techniques included qPCR, Western blot, immunofluorescence, Me-RIP, RIP, dual-luciferase reporter assays, RNA stability analysis, and CFU enumeration.
RESULTS: METTL14 level was significantly decreased in PBMCs of TB patients and in Mtb-infected macrophages. Overexpression of METTL14 restored autophagic flux, as evidenced by increased LC3 puncta, elevated Beclin-1 and ULK1 levels, and enhanced p62 degradation. Mechanistically, METTL14 mediated m6A modification of ULK1 mRNA, which was recognized by YTHDF1 to stabilize the transcript. Silencing ULK1 abrogated METTL14-induced autophagic flux, while pharmacological inhibition of autophagy reversed the suppression of intracellular Mtb survival by METTL14.
CONCLUSION: These findings identify METTL14 as a key epitranscriptomic regulator of autophagic flux in macrophages during Mtb infection. By promoting m6A modification and stabilization of ULK1 mRNA, METTL14 restores autophagic flux and restricts bacterial persistence, highlighting a potential therapeutic target for TB.