ILF and vReD pathways cooperate to control lysosomal transporter protein lifetimes

Abstract

Lysosomal nutrient transporter proteins move lumenal products of biomaterial catabolism to the cytoplasm for reuse by the cell. Two mechanisms control their lifetimes: the ILF (IntraLumenal Fragment) and vReD (Vacuole REcycling and Degradation) pathways. But it is not clear if they function independently. Using S. cerevisiae as a model, here we show that the ILF pathway mediates constitutive turnover of the lysine transporter Ypq1 and zinc transporter Cot1--known vReD client proteins--in vivo and in vitro. In contrast, the vReD pathway mediates constitutive degradation of the amino acid transporter Vba4. Activation of TOR with cycloheximide enhances their degradation by these pathways. However, misfolding by heat stress shunts all three into the ILF pathway. Thus, both pathways control individual transporter lifetimes, although only the ILF pathway mediates protein quality control. The pathway chosen depends on protein fate: degradation is imminent by the ILF pathway, whereas the vReD pathway permits reuse.\n\nHIGHLIGHTS and eTOC BLURBO_LIvReD and ILF pathways control Ypq1, Cot1 and Vba4 lifetimes\nC_LIO_LIILF pathway constitutively degrades Ypq1 and Cot1, vReD degrades Vba4\nC_LIO_LITOR activation stimulates protein degradation by both pathways\nC_LIO_LIILF pathway clears all misfolded proteins for quality control\nC_LI\n\nTwo mechanisms degrade lysosome transporter proteins but it is not clear how each contributes to their lifetimes for organelle homeostasis or remodeling. Here McNally and Brett show that the transporters Cot1, Ypq1 and Vba4 can be selectively degraded by the ILF (IntraLumenal Fragment) pathway or vReD (Vacuole REcycling and Degradation) pathway depending on stimulus. However, only the ILF pathway mediates protein quality control.