AI Article Synopsis
- The human peptide LL-37 can trigger autophagy in macrophages, but its effectiveness varies based on post-translational modifications (PTMs) and its cellular source.
- Neutrophil-derived LL-37 was modified and did not induce autophagy, while macrophage-derived LL-37, mostly native, was effective in initiating this process.
- The presence of an intact N-terminal di-leucine motif in LL-37 is essential for autophagy activation, highlighting how modifications can influence its role in infection and inflammation.
Article Abstract
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.
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