The TORC1 kinase signaling complex is a key determinant of cell growth that senses nutritional status and responds by coordinating diverse cellular processes including transcription, translation, and autophagy. Here, we demonstrate that TORC1 modulates the composition of plasma membrane (PM) proteins by regulating ubiquitin-mediated endocytosis. The mechanism involves the Npr1 kinase, a negative regulator of endocytosis that is itself negatively regulated by TORC1. We show that Npr1 inhibits the activity of Art1, an arrestin-like adaptor protein that promotes endocytosis by targeting the Rsp5 ubiquitin ligase to specific PM cargoes. Npr1 antagonizes Art1-mediated endocytosis via N-terminal phosphorylation, a modification that prevents Art1 association with the PM. Thus, our study adds ubiquitin ligase targeting and control of endocytosis to the known effector mechanisms of TORC1, underscoring how TORC1 coordinates ubiquitin-mediated endocytosis with protein synthesis and autophagy in order to regulate cell growth.

From the moment of cotranslational insertion into the lipid bilayer of the endoplasmic reticulum (ER), newly synthesized integral membrane proteins are subject to a complex series of sorting, trafficking, quality control, and quality maintenance systems. Many of these processes are intimately controlled by ubiquitination, a posttranslational modification that directs trafficking decisions related to both the biosynthetic delivery of proteins to the plasma membrane (PM) via the secretory pathway and the removal of proteins from the PM via the endocytic pathway. Ubiquitin modification of integral membrane proteins (or "cargoes") generally acts as a sorting signal, which is recognized, captured, and delivered to a specific cellular destination via specialized trafficking events. By affecting the quality, quantity, and localization of integral membrane proteins in the cell, defects in these processes contribute to human diseases, including cystic fibrosis, circulatory diseases, and various neuropathies. This review summarizes our current understanding of how ubiquitin modification influences cargo trafficking, with a special emphasis on mechanisms of quality control and quality maintenance in the secretory and endocytic pathways.

Despite its central role in protein degradation little is known about the molecular mechanisms that sense, maintain, and regulate steady state concentration of ubiquitin in the cell. Here, we describe a novel mechanism for regulation of ubiquitin homeostasis that is mediated by phosphorylation of ubiquitin at the Ser57 position. We find that loss of Ppz phosphatase activity leads to defects in ubiquitin homeostasis that are at least partially attributable to elevated levels of Ser57 phosphorylated ubiquitin. Phosphomimetic mutation at the Ser57 position of ubiquitin conferred increased rates of endocytic trafficking and ubiquitin turnover. These phenotypes are associated with bypass of recognition by endosome-localized deubiquitylases -including Doa4 which is critical for regulation of ubiquitin recycling. Thus, ubiquitin homeostasis is significantly impacted by the rate of ubiquitin flux through the endocytic pathway and by signaling pathways that converge on ubiquitin itself to determine whether it is recycled or degraded in the vacuole.