ZNRF1 Mediates Epidermal Growth Factor Receptor Ubiquitination to Control Receptor Lysosomal Trafficking and Degradation
Journal
Frontiers in Cell and Developmental biology
Journal Volume
9
Date Issued
2021
Author(s)
Shen, Chia-Hsing
Chou, Chih-Chang
Lai, Ting-Yu
Hsu, Jer-En
Lin, You-Sheng
Liu, Huai-Yu
Chen, Yan-Kai
Ho, I-Lin
Hsu, Pang-Hung
Chuang, Tsung-Hsien
Abstract
Activation of the epidermal growth factor receptor (EGFR) is crucial for development, tissue homeostasis, and immunity. Dysregulation of EGFR signaling is associated with numerous diseases. EGFR ubiquitination and endosomal trafficking are key events that regulate the termination of EGFR signaling, but their underlying mechanisms remain obscure. Here, we reveal that ZNRF1, an E3 ubiquitin ligase, controls ligand-induced EGFR signaling via mediating receptor ubiquitination. Deletion of ZNRF1 inhibits endosome-to-lysosome sorting of EGFR, resulting in delayed receptor degradation and prolonged downstream signaling. We further demonstrate that ZNRF1 and Casitas B-lineage lymphoma (CBL), another E3 ubiquitin ligase responsible for EGFR ubiquitination, mediate ubiquitination at distinct lysine residues on EGFR. Furthermore, loss of ZNRF1 results in increased susceptibility to herpes simplex virus 1 (HSV-1) infection due to enhanced EGFR-dependent viral entry. Our findings identify ZNRF1 as a novel regulator of EGFR signaling, which together with CBL controls ligand-induced EGFR ubiquitination and lysosomal trafficking.
Subjects
ZNRF1; epidermal growth factor receptor (EGFR); herpes simplex virus 1 (HSV-1); lysosomal trafficking; ubiquitination
SDGs
Other Subjects
benzyloxycarbonylleucylleucylleucinal; chloroquine; epidermal growth factor receptor; ESCRT protein; lysosome associated membrane protein 1; oncolytic virus; short hairpin RNA; ubiquitin protein ligase E3; ubiquitin protein ligase E3 ZNRF1; unclassified drug; A-549 cell line; actin filament; amino acid sequence; Article; autophosphorylation; carboxy terminal sequence; cell differentiation; cell migration; cell surface; comparative study; controlled study; CRISPR-CAS9 system; EGFR signaling; endosome; gene deletion; gene expression; gene silencing; genetic susceptibility; HEK293T cell line; human; Human alphaherpesvirus 1; human cell; immunoblotting; immunofluorescence; immunoprecipitation; indel mutation; lysosome; malignant neoplasm; NCI-H3255 cell line; nonhuman; off-target effect; oncolytic virotherapy; protein degradation; protein expression; real time polymerase chain reaction; RNA isolation; ubiquitination
Type
journal article