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BLOC1S1 Attenuates B. Melitensis 16M LPS‐Triggered Autophagy by Spatial Confinement of TDP‐43

Shicheng Wan,Miao Han,Mengfei Zhang,Wenbo Chen,Fangde Xie,Xuan Luo,Wenping Wu,Congliang Wang,Donghui Yang,Bin Han,Haijing Zhu,Haisheng Yu,Na Li,Jinlian Hua

Published 2025 in Advancement of science

ABSTRACT

Biogenesis of lysosome‐related organelles complex 1 subunit 1 (BLOC1S1) is considered to have anti‐Brucella potential. However, the effect of BLOC1S1 on Brucella autophagy has not yet been studied. This study investigates the interplay between Brucella lipopolysaccharide (LPS) and BLOC1S1 in modulating autophagy within goat spermatogonial stem cells (mGSCs‐I‐SB). Using LPS from B. melitensis 16M, its capacity is demonstrated to induce AMPK‐dependent autophagy, contrasting with Escherichia coli LPS, which shows no significant effect. Mechanistically, B. melitensis 16M LPS activates AMPK signaling, elevates LC3B‐II/LC3B‐I ratios, and upregulates lysosomal and pro‐inflammatory genes. BLOC1S1 overexpression attenuates autophagy, reducing autolysosome formation (TEM) and LC3B‐II/I ratio. RNA sequencing and proteomic analyses reveal BLOC1S1‐mediated transcriptional reprogramming of lysosomal pathways and mitochondrial metabolism. Co‐immunoprecipitation and subcellular localization studies reveal that TDP‐43 is a key interacting partner and that BLOC1S1 sequesters TDP‐43 in the cytoplasm, inhibiting its nuclear translocation‐dependent ATG7 mRNA stability and enhancing autophagy. These findings delineate a dual regulatory mechanism: B. melitensis 16M LPS‐driven, AMPK‐dependent autophagy induction, and BLOC1S1‐mediated autophagic suppression through spatial control of TDP‐43. These results advance understanding of host‐pathogen interactions in brucellosis and identify BLOC1S1 as a potential therapeutic target for bacterial persistence and TDP‐43‐related pathologies.

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