Arsenic disrupts autophagosome-lysosome fusion in a zinc dependent manner across multiple human skin and lung cells lines.

Chronic environmental arsenic exposure causes skin and lung cancers, but the molecular mechanisms are poorly understood. We identified that chronic trivalent inorganic arsenite (iAs) exposure at population relevant 100 nM concentration activates autophagy while suppressing downstream protein degradation. Here, we studied the mechanisms by which environmental iAs exposure uncouples autophagy activation from autophagic protein degradation across human skin and lung cell lines. During autophagy, zinc regulates the critical autophagosome-lysosome fusion (ALF) step connecting initiation to final protein degradation. iAs disrupts zinc dependent processes. Thus, we hypothesized that iAs suppresses autophagy by compromising ALF. We demonstrate that environmental 100 nM iAs exposure specifically targets the ALF step of autophagy to suppress autophagic protein degradation across multiple skin and lung cell line models. We show that iAs suppresses ALF in a zinc dependent manner. Physiological zinc supplementation (1 μM) prevented and rescued against iAs-induced suppression of ALF and autophagic protein degradation in the short and long-term. Our work provides a framework to understand and further investigate the precise molecular mechanisms by which chronic environmental iAs exposure disrupts global protein degradation, thereby inducing proteotoxicity across multiple target tissues and contributing to the observed proteome-wide differential expression patterns during multi-organ carcinogenesis.