LAUSR

NLRP3 inflammasome activation is regulated by autophagy, a process tightly controlled by the ATG16L family proteins. However, the inside mechanisms remain elusive. Although the autophagy‐related protein ATG16L1 has been well characterized, regulation and biological functions of its close homolog ATG16L2 still remain elusive. Here we report that ATG16L2 deficiency attenuates LPS‐induced autophagy flux in macrophages through mediating ATG5‐12‐16L1 complex assembly. Importantly, NLRP3 inflammasome activation is elevated in ATG16L2‐deficient macrophages, which also have defects in mitochondrial integrity and respiration. Finally, ATG16l2 knockout mice are more susceptible to DSS‐induced intestinal damage, which can be ameliorated by inhibition of NLRP3. Collectively, our data demonstrate that ATG16L2 positively regulates autophagy and ATG16L2 could be a potential target for manipulating aberrant NLRP3 inflammasome activation induced inflammatory diseases.