title: Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases.
abstract: Historically, the ubiquitin-proteasome system (UPS) and autophagy pathways were believed to be independent; however, recent data indicate that these pathways engage in crosstalk. To date, the players mediating this crosstalk have been elusive. Here, we show experimentally that EI24 (EI24, autophagy associated transmembrane protein), a key component of basal macroautophagy/autophagy, degrades 14 physiologically important E3 ligases with a RING (really interesting new gene) domain, whereas 5 other ligases were not degraded. Based on the degradation results, we built a statistical model that predicts the RING E3 ligases targeted by EI24 using partial least squares discriminant analysis. Of 381 RING E3 ligases examined computationally, our model predicted 161 EI24 targets. Those targets are primarily involved in transcription, proteolysis, cellular bioenergetics, and apoptosis and regulated by TP53 and MTOR signaling. Collectively, our work demonstrates that EI24 is an essential player in UPS-autophagy crosstalk via degradation of RING E3 ligases. These results indicate a paradigm shift regarding the fate of E3 ligases.
authors.affiliation: a Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center , Yonsei University , Seoul , Republic of Korea.
authors.forename: Sushil
authors.initials: S
authors.lastname: Devkota
authors.affiliation: b Department of New Biology and Center for Plant Aging Research , Institute for Basic Science, DGIST , Daegu , Republic of Korea.
authors.forename: Hyobin
authors.initials: H
authors.lastname: Jeong
authors.affiliation: a Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center , Yonsei University , Seoul , Republic of Korea.
authors.forename: Yunmi
authors.initials: Y
authors.lastname: Kim
authors.affiliation: a Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center , Yonsei University , Seoul , Republic of Korea.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: a Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center , Yonsei University , Seoul , Republic of Korea.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Roh
authors.affiliation: b Department of New Biology and Center for Plant Aging Research , Institute for Basic Science, DGIST , Daegu , Republic of Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: a Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center , Yonsei University , Seoul , Republic of Korea.
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004734:Energy Metabolism; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D054829:RING Finger Domains; D015203:Reproducibility of Results; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C402592:EI24 protein, human; D009687:Nuclear Proteins; D047992:TNF Receptor-Associated Factor 2; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; C505879:TRIM41 protein, human; D044767:Ubiquitin-Protein Ligases; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: E3 ligase; EI24; RING-domain; autophagy; computational biology; proteasome