p62 limits Salmonella Typhimurium in macrophages through its role in cell signalling

TL;DR

The protein p62 helps macrophages fight Salmonella infection by boosting inflammation, independent of its usual role in autophagy.

Contribution

p62 restricts Salmonella in macrophages via a novel mechanism unrelated to Rab32/BLOC-3 or canonical autophagy.

Findings

p62-knockdown macrophages show increased Salmonella survival.

p62 depletion reduces pro-inflammatory responses in infected macrophages.

p62's role in host defense extends beyond autophagy.

Abstract

The intracellular autophagy receptor p62 (also known as Sequestosome-1) plays a dual role in autophagic flux and downstream Toll-like receptor signalling and has been implicated in modulating immune responses. However, its specific function in controlling intracellular bacterial survival, particularly in macrophages, remains less well characterized. Salmonella enterica serovar Typhimurium (S. Tm) is a major global pathogen and a leading cause of gastroenteritis-associated morbidity. We have previously demonstrated that host restriction of S. Tm in macrophages involves the GTPase Rab32 and the BLOC-3 complex. In the present study, we identify a novel interaction between p62 and Rab32. Notably, p62 restricts Salmonella survival independently of the Rab32/BLOC-3 pathway. Indeed, p62-knockdown in macrophages resulted in significantly increased intracellular bacterial survival, an effect that did not correlate with altered recruitment of canonical autophagy-related proteins, as assessed by fluorescence microscopy. Through real-time polymerase chain reaction (RT-qPCR) and infection assays, we further show that p62-depleted macrophages exhibit a dampened pro-inflammatory response, which corresponds with the increased bacterial burden. These findings provide new mechanistic insight into the role of p62 in modulating the macrophage inflammatory response during Salmonella infection, highlighting its contribution to host defence beyond its canonical functions in autophagy.

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