Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands.
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
FEBS Lett. 2022 Feb;596(4):491-509. doi: 10.1002/1873-3468.14280. Epub 2022 Jan 21.
In autophagy, LC3-positive autophagophores fuse and encapsulate the autophagic cargo in a double-membrane structure. In contrast, lipidated LC3 (LC3-II) is directly formed at the phagosomal membrane in LC3-associated phagocytosis (LAP). In this study, we dissected the effects of autophagy inhibitors on LAP. SAR405, an inhibitor of VPS34, reduced levels of LC3-II and inhibited LAP. In contrast, the inhibitors of endosomal acidification bafilomycin A1 and chloroquine increased levels of LC3-II, due to reduced degradation in acidic lysosomes. However, while bafilomycin A1 inhibited LAP, chloroquine did not. Finally, EACC, which inhibits the fusion of autophagosomes with lysosomes, promoted LC3 degradation possibly by the proteasome. Targeting LAP with small molecule inhibitors is important given its emerging role in infectious and autoimmune diseases.
在自噬中，LC3 阳性自噬体融合并将自噬货物包裹在双层膜结构中。相比之下，脂化的 LC3（LC3-II）在 LC3 相关吞噬作用（LAP）中直接在吞噬体膜上形成。在这项研究中，我们剖析了自噬抑制剂对 LAP 的影响。VPS34 的抑制剂 SAR405 降低了 LC3-II 的水平并抑制了 LAP。相比之下，内体酸化的抑制剂巴弗洛霉素 A1 和氯喹增加了 LC3-II 的水平，这是由于酸性溶酶体中降解减少所致。然而，巴弗洛霉素 A1 抑制了 LAP，而氯喹没有。最后，EACC，它抑制自噬体与溶酶体的融合，可能通过蛋白酶体促进 LC3 的降解。用小分子抑制剂靶向 LAP 很重要，因为它在感染和自身免疫性疾病中的作用正在不断涌现。
