Human GBP4 promotes TRIM21-BIP-dependent autophagy to restrict M. tuberculosis infection by preventing SORT1-mediated progranulin degradation

作者：Qinglong Guo, Jing Bi, Yu Fu, 吕松 Lü Song, Haojia Wu, Xi Chen, Yaqi Gong, Carl G. Feng, Guoliang Zhang · 发表于：Cell Reports · 年份：2026 · DOI：10.1016/j.celrep.2026.117739 · 研究领域：Autophagy in Disease and Therapy、Amyotrophic Lateral Sclerosis Research、interferon and immune responses

Interferons (IFNs) are potent antimicrobial cytokines. However, effector mechanisms mediating their function in humans are poorly understood, partly because IFNs can induce numerous effector molecules. While guanylate-binding proteins (GBPs) are IFN-inducible, their role in cell-autonomous resistance to intracellular pathogens is incompletely understood. We demonstrate that human GBP1-5 significantly inhibits intracellular Mycobacterium tuberculosis (Mtb) survival, but only GBP4 mediates autophagy. GBP4 facilitates Mtb containment by promoting lysosomal acidification and autophagy via type Ⅰ IFN-dependent TFEB and FOXO3a activation. Mechanistically, GBP4 binds progranulin (GRN), reducing SORT1-mediated GRN lysosomal degradation. Moreover, GBP4 facilitates the GBP4-GRN-BIP-AKT complex assembly while inhibiting the GBP4-BIP-TRIM21 complex formation, thereby enhancing GRN-mediated BIP accumulation and AKT degradation. This leads to AKT inhibition, and concomitant TFEB and FOXO3a activation. GRN, BIP, AKT, and TRIM21 are essential for GBP4-mediated mycobactericidal activity. Our study uncovers a key role for GBP4 in regulating cell-autonomous resistance in human macrophages and may facilitate the development of host-directed therapies against tuberculosis (TB).