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- Title
Autophagy initiation triggers p150<sup>Glued</sup>–AP-2β interaction on the lysosomes and facilitates their transport.
- Authors
Tempes, Aleksandra; Bogusz, Karolina; Brzozowska, Agnieszka; Weslawski, Jan; Macias, Matylda; Tkaczyk, Oliver; Orzoł, Katarzyna; Lew, Aleksandra; Calka-Kresa, Malgorzata; Bernas, Tytus; Szczepankiewicz, Andrzej A.; Mlostek, Magdalena; Kumari, Shiwani; Liszewska, Ewa; Machnicka, Katarzyna; Bakun, Magdalena; Rubel, Tymon; Malik, Anna R.; Jaworski, Jacek
- Abstract
The endocytic adaptor protein 2 (AP-2) complex binds dynactin as part of its noncanonical function, which is necessary for dynein-driven autophagosome transport along microtubules in neuronal axons. The absence of this AP-2-dependent transport causes neuronal morphology simplification and neurodegeneration. The mechanisms that lead to formation of the AP-2-dynactin complex have not been studied to date. However, the inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) enhances the transport of newly formed autophagosomes by influencing the biogenesis and protein interactions of Rab-interacting lysosomal protein (RILP), another dynein cargo adaptor. We tested effects of mTORC1 inhibition on interactions between the AP-2 and dynactin complexes, with a focus on their two essential subunits, AP-2β and p150Glued. We found that the mTORC1 inhibitor rapamycin enhanced p150Glued–AP-2β complex formation in both neurons and non-neuronal cells. Additional analysis revealed that the p150Glued–AP-2β interaction was indirect and required integrity of the dynactin complex. In non-neuronal cells rapamycin-driven enhancement of the p150Glued–AP-2β interaction also required the presence of cytoplasmic linker protein 170 (CLIP-170), the activation of autophagy, and an undisturbed endolysosomal system. The rapamycin-dependent p150Glued–AP-2β interaction occurred on lysosomal-associated membrane protein 1 (Lamp-1)-positive organelles but without the need for autolysosome formation. Rapamycin treatment also increased the acidification and number of acidic organelles and increased speed of the long-distance retrograde movement of Lamp-1-positive organelles. Altogether, our results indicate that autophagy regulates the p150Glued–AP-2β interaction, possibly to coordinate sufficient motor-adaptor complex availability for effective lysosome transport.
- Subjects
AUTOPHAGY; ADAPTOR proteins; MEMBRANE proteins; MICROTUBULES; LYSOSOMES; PROTEIN-protein interactions; INTRACELLULAR membranes; COATED vesicles
- Publication
Cellular & Molecular Life Sciences, 2024, Vol 81, Issue 1, p1
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-024-05256-6