Ubiquitin‐ligase AIP4 controls differential ubiquitination and stability of isoforms of the scaffold protein ITSN1

Abstract

At present, the role of ubiquitination of cargoes internalized from the plasma membrane is better understood than the consequences of ubiquitination of proteins comprising the endocytic machinery. Here, we show that the E3 ubiquitin ligase AIP4/ITCH contributes to the differential ubiquitination of isoforms of the endocytic scaffold protein intersectin1 (ITSN1). The major isoform ITSN1-s is monoubiquitinated, whereas the minor one, ITSN1-22a undergoes a combination of mono- and oligoubiquitination. The monoubiquitination is required for ITSN1-s stability, whereas the oligoubiquitination of ITSN1-22a causes its proteasomal degradation. This explains the observed low abundance of the minor isoform in cells. Thus, different modes of ubiquitination regulated by AIP4 have opposite effects on ITSN1 isoform stability.

Role of the ubiquitin ligase ITCH in clathrin-mediated endocytosis of the epidermal growth factor receptor

“…By binding the PRR of both CBL and its inhibitor sprouty 2, intersectin disrupts the sprouty 2-CBL interaction, leading to an enhanced EGFR signaling (28). The isoform 1s of intersectin is directly monoubiquitinated by ITCH, a modification that does not lead to its degradation (29).…”