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Long-chain S-acylation is a key modulator during the macrophage inflammatory response

ABSTRACT: Long-chain S-acylation is a reversible lipid modification critical for regulating protein localization, stability, and signaling, yet its role in macrophage-mediated inflammation remains incompletely understood. Here, we combine stable isotope labeling by amino acids in cell culture (SILAC) with site-specific acyl-biotin exchange (ssABE) to generate a comprehensive map of the long-chain S-acylation landscape in THP-1 macrophages polarized to M0 and M1 states. Our quantitative proteomics reveal polarization-specific S-acylation patterns and uncover numerous inflammation-induced modification sites, including novel S-acyl modiforms, which are distinct S-acylated variants of the same proteinsuch as WARS (C305/C309), highlighting their potential functional relevance in macrophage activation. Pharmacological inhibition of S-acylation with the broad-spectrum inhibitor 2-bromopalmitate suppresses secretion of key pro-inflammatory chemokines (CXCL9, CXCL10, CCL4) and disrupts IDO1-mediated tryptophan catabolism, while Palmostatin B stabilizes S-acylation mainly on GPCR signaling proteins as well as Toll-like receptor 1/6. Together, these findings position long-chain S-acylation as a key regulatory mechanism during macrophage activation, and a promising target for therapeutic intervention in inflammatory disease.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte

DISEASE(S): Inflammation

SUBMITTER: Anneroos Nederstigt

LAB HEAD: Marc Pieter

PROVIDER: PXD066221 | Pride | 2026-06-10

REPOSITORIES: Pride

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			Action	DRS
	APT_inhibition_TP.zip	Other
	APT_inhibition_TP_PalmB_rep1.raw	Raw
	APT_inhibition_TP_PalmB_rep2.raw	Raw
	APT_inhibition_TP_PalmB_rep3.raw	Raw
	APT_inhibition_TP_vehicle_rep1.raw	Raw

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