Abstract
Endocytosis is regulated in response to changing environmental conditions to adjust plasma membrane (PM) protein composition for optimal cell growth. Protein networks involved in cargo capture and sorting, membrane sculpting and deformation, and vesicle scission have been well-characterized, but less is known about the networks that sense extracellular cues and relay signals to trigger endocytosis of specific cargo. Hal4 and Hal5 are yeast Snf1-related kinases that were previously reported to regulate nutrient transporter stability by an unknown mechanism. Here we demonstrate that loss of Hal4 and Hal5 activates endocytosis of many different kinds of PM proteins, including Art1-mediated and Art1-independent endocytic events. Acute inhibition of Hal5 in the absence of Hal4 triggers rapid endocytosis, suggesting that Hal kinases function in a nutrient-sensing relay upstream of the endocytic response. Interestingly, Hal5 localizes to the PM, but shifts away from the cell surface in response to stimulation with specific nutrients. We propose that Hal5 functions as a nutrient-responsive regulator of PM protein stability, antagonizing endocytosis and promoting stability of endocytic cargos at the PM in nutrient-limiting conditions.
Highlights
Complex signaling networks sense and integrate information about the extracellular environment to coordinate diverse biological processes as part of the adaptive growth response
Our data indicates that Hal kinases function broadly in the regulation of many different classes of endocytic cargo
As with Pma2, we found that loss of Hal kinases did not affect the localization of the peripheral plasma membrane protein Pil1—a BAR domain protein and a core structural component of eisosomes [48, 49]
Summary
Complex signaling networks sense and integrate information about the extracellular environment to coordinate diverse biological processes as part of the adaptive growth response. Substrate (or ligand) engagement with cognate transporters (or receptors) selectively stimulates internalization by endocytosis and subsequent sorting on endosomes for delivery to the lysosome (or vacuole) for degradation This type of endocytic downregulation has been described for many major facilitator family nutrient transporters in Saccharomyces cerevisiae, including Mup (a high-affinity methionine transporter) [1, 2], Can (a high-affinity arginine transporter) [3, 4], and Fur (a high-affinity uracil transporter) [5,6,7,8]. Cargo ubiquitylation is sufficient for capture by ubiquitinbinding elements in the endocytic machinery, and understanding how extracellular cues are sensed and signals are relayed to trigger ubiquitylation of specific cargo at the PM will be critical for understanding the molecular basis for specificity in endocytic responses [12,13,14]
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