Abstract
Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a component of the ESCRT-0 protein complex that captures ubiquitylated cargo proteins and sorts them to the lysosomal pathway. Although Hrs acts as a key transporter for ubiquitin-dependent endosomal sorting, we previously reported that Hrs is also involved in ubiquitin-independent endosomal sorting of interleukin-2 receptor β (IL-2Rβ). Here, we show direct interactions between bacterially expressed Hrs and interleukin-4 receptor α (IL-4Rα), indicating that their binding is not required for ubiquitylation of the receptors, similar to the case for IL-2Rβ. Examinations of the Hrs binding regions of the receptors reveal that a hydrophobic amino acid cluster in both IL-2Rβ and IL-4Rα is essential for the binding. Whereas the wild-type receptors are delivered to LAMP1-positive late endosomes, mutant receptors lacking the hydrophobic amino acid cluster are sorted to lysobisphosphatidic acid-positive late endosomes rather than LAMP1-positive late endosomes. We also show that the degradation of these mutant receptors is attenuated. Accordingly, Hrs functions during ubiquitin-independent endosomal sorting of the receptors by recognizing the hydrophobic amino acid cluster. These findings suggest the existence of a group of cargo proteins that have this hydrophobic amino acid cluster as a ubiquitin-independent sorting signal.
Highlights
Endosomal sorting of cell surface receptors plays a key role in the destiny of the receptors, as some receptors in sorting endosomes are recycled back to the plasma membrane, whereas others are delivered to the lysosome for degradation and attenuation of receptor-mediated signal transduction
Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) acts as a key transporter for ubiquitin-dependent endosomal sorting, we previously reported that Hrs is involved in ubiquitin-independent endosomal sorting of interleukin-2 receptor  (IL-2R)
Ubiquitin-independent Endosomal Sorting Signal tive late endosomes, and the degradation rate of the IL-2 receptor (IL-2R) mutant was diminished compared with that of wild-type IL-2R [23]. These findings led us to propose the following two hypotheses; 1) there is a group of cytokine receptors that interact with Hrs in a ubiquitin-independent manner, because it does not follow that only IL-2R interacts with Hrs in this manner, and 2) there is a motif that interacts with Hrs in the cytoplasmic region of such receptors
Summary
Endosomal sorting of cell surface receptors plays a key role in the destiny of the receptors, as some receptors in sorting endosomes are recycled back to the plasma membrane, whereas others are delivered to the lysosome for degradation and attenuation of receptor-mediated signal transduction. Hrs functions during ubiquitin-independent endosomal sorting of the receptors by recognizing the hydrophobic amino acid cluster.
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