Potential model of Rsp5/NEDD4 and ESCRT-dependent clearance of cytoplasmic TDP-43. We speculate that TDP-43 is subject to K63 polyubiquitination by Rsp5/NEDD4, which may promote recognition and remodeling by the “Ub-segregase” chaperone VCP and/or subsequent binding to ESCRT factors via their Ub-binding domains. This may lead to TDP-43 internalization within MVB intraluminal vesicles and subsequent degradation in lysosomes (or MVBs themselves). While our data indicate full-length TDP-43 degrades via our endolysosomal pathway, it remains unclear what, or if, specific TDP-43 physical states (e.g., cleaved/modified forms, aggregates) preferentially degrade via this or other reported TDP-43 clearance mechanisms (e.g., macroautophagy and proteasome).