Rekha Rokeya Sultana, Padhi Avinash, Frengen Nicolai, Hauenstein Julia, Végvári Ákos, Agerberth Birgitta, Månsson Robert, Guðmundsson Guðmundur H, Bergman Peter
Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Institutet, Huddinge, Stockholm, Sweden.
Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet, Stockholm, Sweden.
Cell Rep. 2025 Jan 28;44(1):115031. doi: 10.1016/j.celrep.2024.115031. Epub 2024 Dec 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.
人源杀菌肽LL-37可诱导人巨噬细胞发生自噬。不同的翻译后修饰（PTM），如瓜氨酸化、乙酰化和甲酰化，会影响LL-37，但它们对自噬的影响尚不清楚。因此，我们着手研究细胞来源如何影响LL-37的PTM以及随后对自噬起始的影响。与巨噬细胞释放的LL-37不同，中性粒细胞释放的LL-37无法诱导自噬。质谱分析显示中性粒细胞来源的LL-37存在修饰，尤其是在N端，而巨噬细胞来源的LL-37大多保持天然状态。天然的LL-37可启动自噬，而甲酰化和乙酰化形式则不能。缺少N端双亮氨酸基序或被双丙氨酸取代的截短肽不能启动自噬。在二肽基肽酶-1基因失活的巨噬细胞中，天然的LL-37无法启动自噬。LL-37中完整的N端双亮氨酸基序对自噬起始至关重要，修饰会消除这种作用。该途径为调节LL-37在感染或炎症中的作用提供了一种新方法。
