Abstract 2332 Small GTPase Arl4A attenuates EGFR degradation by binding to the ESCRT-II-complex

ADP-ribosylation factor (Arf)-like protein 4A (Arl4A), an Arf-like small GTPase, functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration. Arl4A also localizes at endosomal compartments, but its role at these sites remains unknown. We address this issue in the current study by finding that Arl4A inhibits the endosomal transport of the epidermal growth factor receptor (EGFR) to attenuate its degradation at the lysosome, resulting in enhanced receptor-mediated signaling. Mechanistically, we elucidate that Arl4A decreases the association of the deubiquitinating enzyme USP8/UBPY with endosomal sorting complex required for transport (ESCRT)-III, resulting in the delayed de-ubiquitination and degradation of EGFR. Arl4A also interacts with VPS36, a component of the ESCRT-II-complex. This interaction promotes the recruitment of VPS36 to the late endosome, also resulting in the delayed de-ubiquitination and degradation of EGFR. These findings identify for the first time a role for Arl4A at endosomal compartments, acting through two complementary mechanisms to inhibit EGFR de-ubiquitination, resulting in reduced EGFR degradation and enhanced receptor signaling. Intracellular signaling through EGFR affects multiple cellular processes. Thus, as our study has revealed new modes of regulating this signaling by modulating the endosomal transport of EGFR. This work was supported by grants from the National Health Research Institutes (NHRI) of Taiwan (NHRI-EX110-10902B1), the Ministry of Science and Technology in Taiwan (NSTC111-2634-F-002-017), and the Center of Precision Medicine from the Ministry of Education in Taiwan awarded to F.S.L.