Human autophagy gene ATG16L1 is post-transcriptionally regulated by MIR142-3p

Zili Zhai, Feng Wu, Fengshi Dong, Alice Y. Chuang, Jeannette S. Messer, David L. Boone, John H. Kwon

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40 Scopus citations

Abstract

Multiple genetic studies have implicated the autophagy-related gene, ATG16L1, in the pathogenesis of Crohn disease (CD). While CD-related research on ATG16L1 has focused on the functional significance of ATG16L1 genetic variations, the mechanisms underlying the regulation of ATG16L1 expression are unclear. Our laboratory has described that microRNAs (miRNAs), key regulators of gene expression, are dysregulated in CD. Here, we report miRNA-mediated regulation of ATG16L1 in colonic epithelial cells as well as Jurkat T cells. Dual luciferase reporter assays following the transfection of vectors containing the ATG16L1 3′-untranslated region (3′ UTR) or truncated 3′UTR fragments suggest that the first half of ATG16L1 3′UTR in the 5′ end is more functional for miRNA targeting. Of 5 tested miRNAs with putative binding sites within the region, MIR142-3p, upon transient overexpression in the cells, resulted in decreased ATG16L1 mRNA and protein levels. Further observation demonstrated that the luciferase reporter vector with a mutant MIR142-3p binding sequence in the 3′UTR was unresponsive to the inhibitory effect of MIR142-3p, suggesting ATG16L1 is a gene target of MIR142-3p. Moreover, the regulation of ATG16L1 expression by a MIR142-3p mimic blunted starvation-and L18-MDP-induced autophagic activity in HC T116 cells. Additionally, we found that a MIR142-3p inhibitor enhanced starvation-induced autophagy in Jurkat T cells. Our study reveals MIR142-3p as a new autophagy-regulating small molecule by targeting ATG16L1, implying a role of this miRNA in intestinal inflammation and CD.

Original languageEnglish (US)
Pages (from-to)468-479
Number of pages12
JournalAutophagy
Volume10
Issue number3
DOIs
StatePublished - Mar 2014

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Keywords

  • ATG16L1
  • Autophagy
  • Crohn disease
  • MIR142-3p
  • MicroRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Zhai, Z., Wu, F., Dong, F., Chuang, A. Y., Messer, J. S., Boone, D. L., & Kwon, J. H. (2014). Human autophagy gene ATG16L1 is post-transcriptionally regulated by MIR142-3p. Autophagy, 10(3), 468-479. https://doi.org/10.4161/auto.27553