Abstract
ABSTRACTHis domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) collaborates with endosomal sorting complexes required for transport (ESCRTs) to sort endosomal cargo into intralumenal vesicles, forming the multivesicular body (MVB). Completion of MVB sorting is accompanied by maturation of the endosome into a late endosome, an event that requires inactivation of the early endosomal GTPase Rab5 (herein referring to generically to all isoforms). Here, we show that HD-PTP links ESCRT function with endosomal maturation. HD-PTP depletion prevents MVB sorting, while also blocking cargo from exiting Rab5-rich endosomes. HD-PTP-depleted cells contain hyperphosphorylated Rabaptin-5 (also known as RABEP1), a cofactor for the Rab5 guanine nucleotide exchange factor Rabex-5 (also known as RABGEF1), although HD-PTP is unlikely to directly dephosphorylate Rabaptin-5. In addition, HD-PTP-depleted cells exhibit Rabaptin-5-dependent hyperactivation of Rab5. HD-PTP binds directly to Rabaptin-5, between its Rabex-5- and Rab5-binding domains. This binding reaction involves the ESCRT-0/ESCRT-III binding site in HD-PTP, which is competed for by an ESCRT-III peptide. Jointly, these findings indicate that HD-PTP may alternatively scaffold ESCRTs and modulate Rabex-5–Rabaptin-5 activity, thereby helping to coordinate the completion of MVB sorting with endosomal maturation.
Highlights
Plasma membrane proteins that are internalised by endocytosis enter the early endosome and are subject to a critical decision
His Domain Protein Tyrosine Phosphatase (HD-PTP) binds directly to Rabaptin-5, between its Rabex-5 and Rab5 binding domains. This binding reaction involves the Endosomal Sorting Complexes Required for Transport (ESCRTs)-0/ESCRT-III binding site in HD-PTP and is competed by an ESCRT-III peptide. These findings indicate that HD-PTP may alternately scaffold ESCRTs and modulate Rabex5/Rabaptin-5 activity, thereby helping to coordinate the completion of multivesicular body (MVB) sorting with endosomal maturation
We have previously reported that siRNA-mediated depletion of HD-PTP prevents lysosomal degradation of EGF (Doyotte et al, 2008) and inhibits the MVB sorting of epidermal growth factor receptor (EGFR) stimulated by EGF (Ali et al, 2013)
Summary
Plasma membrane proteins that are internalised by endocytosis enter the early endosome and are subject to a critical decision. Within the early endosome, ubiquitinated EGFR (Galcheva-Gargova et al, 1995) engages the ESCRT (Endosomal Sorting Complexes Required for Transport) pathway (Eden et al, 2012; Raiborg and Stenmark, 2009; Tabernero and Woodman, 2018). This series of protein complexes includes ESCRTs-0, -I and -II, ubiquitin-binding complexes that sequester ubiquitinated cargo and pass it to ESCRT-III (Frankel and Audhya, 2018; Henne et al, 2011; Piper et al, 2014). ESCRT-III is a generic membrane curvatureinducing polymer that combines with the downstream AAA ATPase VPS4 to drive reverse topology membrane scission (Gatta and Carlton, 2019; Henne et al, 2013; McCullough et al, 2018; Pfitzner et al, 2021; Remec Pavlin and Hurley, 2020; Zhen et al, 2021), and at the MVB completes ILV formation (Raiborg and Stenmark, 2009; Vietri et al, 2020)
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