TBK1 kinase addiction in lung cancer cells is mediated via autophagy of Tax1bp1/Ndp52 and non-canonical NF-κB signalling

PLoS One. 2012;7(11):e50672. doi: 10.1371/journal.pone.0050672. Epub 2012 Nov 29.

Abstract

K-Ras dependent non-small cell lung cancer (NSCLC) cells are 'addicted' to basal autophagy that reprograms cellular metabolism in a lysosomal-sensitive manner. Here we demonstrate that the xenophagy-associated kinase TBK1 drives basal autophagy, consistent with its known requirement in K-Ras-dependent NSCLC proliferation. Furthermore, basal autophagy in this context is characterised by sequestration of the xenophagy cargo receptor Ndp52 and its paralogue Tax1bp1, which we demonstrate here to be a bona fide cargo receptor. Autophagy of these cargo receptors promotes non-canonical NF-κB signalling. We propose that this TBK1-dependent mechanism for NF-κB signalling contributes to autophagy addiction in K-Ras driven NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics
  • Autophagy / physiology*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line
  • Fluorescent Antibody Technique
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lentivirus
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Transcription Factor RelB / genetics
  • Transcription Factor RelB / metabolism

Substances

  • CALCOCO2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • TAX1BP1 protein, human
  • Transcription Factor RelA
  • Transcription Factor RelB
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human