Deficiency of GABARAP but not its Paralogs Causes Enhanced EGF-induced EGFR Degradation

Cells. 2020 May 22;9(5):1296. doi: 10.3390/cells9051296.

Abstract

The γ-aminobutyric acid type A receptor-associated protein (GABARAP) and its close paralogs GABARAPL1 and GABARAPL2 constitute a subfamily of the autophagy-related 8 (Atg8) protein family. Being associated with a variety of dynamic membranous structures of autophagic and non-autophagic origin, Atg8 proteins functionalize membranes by either serving as docking sites for other proteins or by acting as membrane tethers or adhesion factors. In this study, we describe that deficiency for GABARAP alone, but not for its close paralogs, is sufficient for accelerated EGF receptor (EGFR) degradation in response to EGF, which is accompanied by the downregulation of EGFR-mediated MAPK signaling, altered target gene expression, EGF uptake, and EGF vesicle composition over time. We further show that GABARAP and EGFR converge in the same distinct compartments at endogenous GABARAP expression levels in response to EGF stimulation. Furthermore, GABARAP associates with EGFR in living cells and binds to synthetic peptides that are derived from the EGFR cytoplasmic tail in vitro. Thus, our data strongly indicate a unique and novel role for GABARAP during EGFR trafficking.

Keywords: Atg8; EGFR; GABARAP; degradation; genome editing; receptor trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins / deficiency*
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy-Related Protein 8 Family / metabolism
  • Cell Line, Tumor
  • Endocytosis / drug effects
  • Endosomes / drug effects
  • Endosomes / metabolism
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism
  • Fluorescent Dyes / metabolism
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Microtubule-Associated Proteins / deficiency*
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Phosphorylation / drug effects
  • Proteasome Inhibitors / pharmacology
  • Proteolysis* / drug effects
  • Sequence Homology, Amino Acid*
  • Signal Transduction / drug effects
  • Transport Vesicles / drug effects
  • Transport Vesicles / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Protein 8 Family
  • Fluorescent Dyes
  • GABARAP protein, human
  • GABARAPL1 protein, human
  • GABARAPL2 protein, human
  • Microtubule-Associated Proteins
  • Proteasome Inhibitors
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors