The ER-phagy receptor FAM134B is targeted by Salmonella Typhimurium to promote infection

Damián Gatica, Reham M. Alsaadi, Rayan El Hamra, Boran Li, Rudolf Mueller, Makoto Miyazaki, Qiming Sun, Subash Sad and Ryan C. Russell ()
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Damián Gatica: University of Ottawa
Reham M. Alsaadi: University of Ottawa
Rayan El Hamra: University of Ottawa
Boran Li: The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Rudolf Mueller: University of Ottawa
Makoto Miyazaki: University of Colorado Denver
Qiming Sun: The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Subash Sad: University of Ottawa
Ryan C. Russell: University of Ottawa

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum (hereafter referred to as ER-phagy) is a homeostatic mechanism, controlling ER size, the removal of misfolded protein aggregates, and organelle damage. ER-phagy can also be stimulated by pathogen infection. However, the link between ER-phagy and bacterial infection remains poorly understood, as are the mechanisms evolved by pathogens to escape the effects of ER-phagy. Here, we show that Salmonella enterica serovar Typhimurium inhibits ER-phagy by targeting the ER-phagy receptor FAM134B, leading to a pronounced increase in Salmonella burden after invasion. Salmonella prevents FAM134B oligomerization, which is required for efficient ER-phagy. FAM134B knock-out raises intracellular Salmonella number, while FAM134B activation reduces Salmonella burden. Additionally, we found that Salmonella targets FAM134B through the bacterial effector SopF to enhance intracellular survival through ER-phagy inhibition. Furthermore, FAM134B knock-out mice infected with Salmonella presented severe intestinal damage and increased bacterial burden. These results provide mechanistic insight into the interplay between ER-phagy and bacterial infection, highlighting a key role for FAM134B in innate immunity.

Date: 2025
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DOI: 10.1038/s41467-025-58035-7

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