A549 adenocarcinoma human alveolar basal epithelial cells Salmonella enterica infection Proteomics

ABSTRACT: For decades, the prevailing paradigm has posited that the primary function of proteasome-derived peptides is serving for antigen presentation. The proteasome-cleaved peptides are loaded onto Major Histocompatibility Complex I (MHCI) molecules and serve to elicit T cell-mediated cytotoxicity. Yet, whether the products of proteasomal degradation may play additional roles in modulating immune responses, remains largely unknown. Antimicrobial peptides (AMPs) serve as a first line of defense against invading pathogens. They act quickly to prevent the establishment of infections, providing an initial barrier against microbes before the adaptive immune system can respond. As such, there is a great need in constitutive and bacterial-induced production of AMPs, across numerous tissues. As AMPs are widely distributed across the proteome and may not be readily clipped from their host proteins, degradation mechanisms may facilitate their release and diversity. In this study, we uncover a role for cellular proteasomes in the constitutive generation of proteasome-derived defense peptides (PDDPs) capable of impeding bacterial growth in vitro and in vivo by disrupting bacterial membranes. Further, we found that in response to bacterial infection, the composition and function of cellular proteasomes are altered. Specifically, recruitment of the regulatory cap, PSME3 onto proteasomes, increases tryptic-like cleavages of peptides, which in turn, enhances the production of PDDPs with cationic termini as a defense mechanism. In silico prediction of proteome-wide proteasomal cleavage identified more than 270,000 putative peptides that may be generated en route to degradation and bear cationic properties to serve as a first line of defense. Our findings suggest that PDDPs play a previously unrecognized fundamental role in cell-autonomous innate immunity against pathogens.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human) Escherichia Coli

TISSUE(S): Epithelial Cell

DISEASE(S): Lung Adenocarcinoma

SUBMITTER: Yifat Merbl  

LAB HEAD: Yifat Merbl

PROVIDER: PXD052314 | Pride | 2025-03-07

REPOSITORIES: Pride