Dataset Information

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.

SUBMITTER: Devkota S

PROVIDER: S-EPMC5103340 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases.

Devkota Sushil S Jeong Hyobin H Kim Yunmi Y Ali Muhammad M Roh Jae-Il JI Hwang Daehee D Lee Han-Woong HW

Autophagy 20160819 11

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 ...[more]

PMID: 27541728

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Project description:Accumulative studies revealed that E3 ubiquitin ligases have important roles in colorectal carcinogenesis. The pathogenic mechanisms of colorectal cancer (CRC) initiation and progression are complex and heterogeneous, involving somatic mutations, abnormal gene fusion, deletion or amplification and epigenetic alteration, which may cause aberrant expression or altered function of E3 ligases in CRC. Defects of E3 ligases have been reported to be involved in the molecular etiology and pathogenesis of CRC. The aberrant expressed E3 ligases can function as either oncogenes or tumor suppressors depending on ubiquiting target substrates in CRC. Recently, considerable progress has been made in our understanding of the potential roles of E3 ligase-mediated ubiquitylation in colorectal carcinogenesis. There are mainly two subtypes of E3 ubiquitin ligases in humans, as defined by the presence of either a HECT domain or a RING finger domain on the basis of structural similitude. Most cancer-associated E3 ligases participate in regulating the cell cycle, apoptosis, gene transcription, cell signaling and DNA repair, the critical parts of CRC tumorigenesis. In this review, we have provided a comprehensive summary of abnormally expressed E3 ligases and their related pivotal mechanistic effects in CRC. In particular, we have highlighted the function of RING-type E3 ubiquitin enzymes in modulating cancer signaling pathways, immunity and tumor microenvironment in CRC development and progression; their mechanism(s) of action in CRC involving both ubiquitylation-dependent and ubiquitylation-independent effects; and the potential of RING E3 ligases as molecular biomarkers for predicting patient prognosis and as therapeutic targets in CRC. A better understanding of E3 ligase-mediated substrates' ubiquitylation involved in the development of CRC will provide new insights into the pathophysiology mechanisms of CRC, and unravel novel prognostic markers and therapeutic strategies for CRC.

Dataset Information

Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases.

Publications

Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases.

Similar Datasets

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