TLR-mediated aggresome-like induced structures comprise antimicrobial peptides and attenuate intracellular bacterial survival

Immune cells employ diverse mechanisms for host defense. Macrophages, in response to TLR activation, assemble aggresome-like induced structures (ALIS). Our group has shown TLR4-signaling transcriptionally upregulates p62/sequestome1, which assembles ALIS. We have demonstrated that TLR4-mediated auto...

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Published in:Molecular biology of the cell 2024-03, Vol.35 (3), p.ar34-ar34
Main Authors: Bhatnagar, Anushree, Chopra, Umesh, Raja, Sebastian, Das, Krishanu Dey, Mahalingam, S, Chakravortty, Dipshikha, Srinivasula, Srinivasa Murty
Format: Article
Language:English
Subjects:
Antimicrobial Peptides
Autophagy - physiology
Identification and classification
Macrophages - metabolism
Properties
Proteins
Toll-Like Receptor 4 - genetics
Toll-like receptors
Ubiquitin - metabolism
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Summary:Immune cells employ diverse mechanisms for host defense. Macrophages, in response to TLR activation, assemble aggresome-like induced structures (ALIS). Our group has shown TLR4-signaling transcriptionally upregulates p62/sequestome1, which assembles ALIS. We have demonstrated that TLR4-mediated autophagy is, in fact, selective-autophagy of ALIS. We hypothesize that TLR-mediated autophagy and ALIS contribute to host-defense. Here we show that ALIS are assembled in macrophages upon exposure to different bacteria. These structures are associated with pathogen-containing phagosomes. Importantly, we present evidence of increased bacterial burden, where ALIS assembly is prevented with p62-specific siRNA. We have employed 3D-super-resolution structured illumination microscopy (3D-SR-SIM) and mass-spectrometric (MS) analyses to gain insight into the assembly of ALIS. Ultra-structural analyses of known constituents of ALIS (p62, ubiquitin, LC3) reveal that ALIS are organized structures with distinct patterns of alignment. Furthermore, MS-analyses of ALIS identified, among others, several proteins of known antimicrobial properties. We have validated MS data by testing the association of some of these molecules (Bst2, IFITM2, IFITM3) with ALIS and the phagocytosed-bacteria. We surmise that AMPs enrichment in ALIS leads to their delivery to bacteria-containing phagosomes and restricts the bacteria. Our findings in this paper support hitherto unknown functions of ALIS in host-defense.
ISSN:1059-1524
1939-4586
DOI:10.1091/MBC.E23-09-0347