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TMEM166/EVA1A interacts with ATG16L1 and induces autophagosome formation and cell death

Jia Hu1,2, Ge Li1, Liujing Qu1

  • 1Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 38 Xueyuan Road, Beijing 100191, China.

Cell Death & Disease
|August 5, 2016
PubMed

Insights

EVA1A protein is crucial for autophagosome formation by interacting with ATG16L1 to recruit essential complexes to the membrane. This process also influences programmed cell death via autophagy and apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Autophagy Research

Background:

  • Autophagosome formation relies on ATG proteins, but their membrane recruitment is not fully understood.
  • The precise role of EVA1A (eva-1 homolog A)/TMEM166 in autophagy requires further elucidation.

Purpose of the Study:

  • To investigate the role of EVA1A in autophagosome formation and its underlying molecular mechanism.
  • To explore the relationship between EVA1A, autophagy, and programmed cell death.

Main Methods:

  • Confocal microscopy to observe colocalization of EVA1A with autophagic markers (ZFYVE1, ATG9, LC3B, ATG16L1, ATG5, STX17, RAB7, LAMP1).
  • Gene silencing (EVA1A siRNA) and knockout (Eva1a KO MEFs) to assess the necessity of EVA1A in autophagosome formation.
  • Investigating the dependency on specific autophagy complexes (BECN1-PIK3C3, ATG7, ATG12-ATG5/ATG16L1).
  • Analyzing the contribution of autophagy and apoptosis to EVA1A-induced cell death.

Main Results:

  • EVA1A localizes to autophagosomal membranes and is essential for autophagosome formation, as evidenced by decreased formation in EVA1A-silenced and knockout cells.
  • EVA1A-induced autophagy requires ATG7 and the ATG12-ATG5/ATG16L1 complex but is independent of the BECN1-PIK3C3 complex.
  • EVA1A directly interacts with the WD repeats of ATG16L1 via its C-terminus, promoting ATG12-ATG5/ATG16L1 complex recruitment and enhancing autophagosome biogenesis.
  • Both autophagy and apoptosis contribute to EVA1A-induced cell death, and their inhibition attenuates this effect.

Conclusions:

  • EVA1A plays a critical role in autophagosome formation by mediating the recruitment of the ATG12-ATG5/ATG16L1 complex to autophagic membranes.
  • EVA1A is involved in programmed cell death through both autophagic and apoptotic pathways.
  • This study elucidates a novel molecular mechanism for EVA1A in autophagy and provides insights into its role in cell death pathways.

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