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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
Published on: October 18, 2024
TDCPP disrupts ALG-2/ALIX-mediated ESCRT-III recruitment: Implications for lysosomal membrane repair and
Tingting Li1, Yue Zhang1, Xueman Ding1
1Key Laboratory for Prevention and Control of Emerging Infectious Diseases and Public Health Security, The Xinjiang Production and Construction Corps, School of Medicine, Shihezi University, Shihezi, People's Republic of China; Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (First Affiliated Hospital, School of Medicine, Shihezi University), People's Republic of China.
Abstract:
Tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a prevalent flame retardant, is associated with neurotoxicity linked to lysosomal damage. Timely repair of damaged lysosomal membranes is crucial for cell survival. This study aimed to elucidate the role of endosomal sorting complex required for transport (ESCRT)-dependent lysosomal membrane repair mechanisms in TDCPP-induced neurotoxicity, focusing on the regulatory roles of apoptosis-linked gene 2 (ALG-2) and ALG-2 interacting protein-X (ALIX) in recruiting ESCRT-III complexes. Using in vitro models of TDCPP exposure in the human neuroblastoma cell line SH-SY5Y and murine astrocyte cell line C8-D1A, we found that TDCPP exposure led to impaired lysosomal membrane repair via ESCRT-dependent mechanisms, disrupted lysosomal membrane integrity, and induced apoptosis. This impairment was characterized by: decreased expression of ALG-2, ALIX, and the ESCRT-III subunit - charged multivesicular body protein 4B (CHMP4B); reduced recruitment of CHMP4B mediated by ALG-2/ALIX; increased levels of galectin-3 and cleaved poly (ADP-ribose) polymerase (Cleaved-PARP); and an elevated apoptosis rate. Notably, ALG-2 and ALIX overexpression reinstated CHMP4B accumulation at injury sites, facilitated lysosomal recovery, and mitigated TDCPP-induced lysosomal membrane damage and apoptosis. These findings indicate that TDCPP interferes with ALG-2/ALIX-mediated ESCRT-III recruitment, leading to defective lysosomal membrane repair. Moreover, ALG-2 and ALIX overexpression attenuated TDCPP-induced lysosomal injury, enhancing cell survival. Our findings reveal a novel mechanism by which TDCPP disrupts lysosomal membrane repair through interference with ALG-2/ALIX-mediated ESCRT-III recruitment, providing the molecular mechanisms of TDCPP-induced neurotoxicity and highlighting potential therapeutic strategies for combating TDCPP toxicity.
