The di-leucine motif in the host defense peptide LL-37 is essential for initiation of autophagy in human macrophages.

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Rekha RS, Padhi A, Frengen N, Hauenstein J, Végvári Á, Agerberth B, Månsson R, Guðmundsson GH, Bergman P

Cell Rep 44 (1) 115031 [2025-01-28; online 2024-12-20]

The human cathelicidin peptide LL-37 induces autophagy in human macrophages. Different post-translational modifications (PTMs) such as citrullination, acetylation, and formylation impact LL-37, yet their effect on autophagy remains unknown. Thus, we set out to study how the cellular source could impact PTM of LL-37 and subsequent effects on autophagy initiation. Neutrophil-released LL-37 failed to induce autophagy, unlike macrophage-released LL-37. Mass spectrometry analysis revealed modifications on neutrophil-derived LL-37, especially at the N terminus, while macrophage-derived LL-37 remained mostly native. Native LL-37 initiated autophagy, while formylated and acetylated versions did not. Truncated peptides lacking the N-terminal di-leucine motif or substituted with di-alanine did not initiate autophagy. Native LL-37 failed to initiate autophagy in macrophages with genetic inactivation of dipeptidyl peptidase-1. An intact N-terminal di-leucine motif in LL-37 was crucial for autophagy initiation, and modifications abrogated the effects. This pathway presents a novel way to regulate the effects of LL-37 in infection or inflammation.

Bioinformatics Support for Computational Resources [Service]

PubMed 39708316

DOI 10.1016/j.celrep.2024.115031

Crossref 10.1016/j.celrep.2024.115031

pii: S2211-1247(24)01382-2