Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Academic Article uri icon

Overview

MeSH

  • Animals
  • Antigens, CD95
  • Autophagy
  • Caveolin 1
  • Humans
  • Membrane Microdomains
  • Mice
  • Mice, Knockout
  • Respiratory Mucosa

MeSH Major

  • Apoptosis
  • Lung
  • Microtubule-Associated Proteins
  • Pulmonary Disease, Chronic Obstructive
  • Pulmonary Emphysema
  • Smoking

abstract

  • Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain-3B (LC3B) as a positive regulator of CS-induced lung epithelial cell death. We now extend these initial observations to explore the mechanism by which LC3B mediates CS-induced apoptosis and emphysema development in vivo. Here, we observed that LC3B(-/-) mice had significantly decreased levels of apoptosis in the lungs after CS exposure, and displayed resistance to CS-induced airspace enlargement, relative to WT littermate mice. We found that LC3B associated with the extrinsic apoptotic factor Fas in lipid rafts in an interaction mediated by caveolin-1 (Cav-1). The siRNA-dependent knockdown of Cav-1 sensitized epithelial cells to CS-induced apoptosis, as evidenced by enhanced death-inducing signaling complex formation and caspase activation. Furthermore, Cav-1(-/-) mice exhibited higher levels of autophagy and apoptosis in the lung in response to chronic CS exposure in vivo. In conclusion, we demonstrate a pivotal role for the autophagic protein LC3B in CS-induced apoptosis and emphysema, suggestive of novel therapeutic targets for COPD treatment. This study also introduces a mechanism by which LC3B, through interactions with Cav-1 and Fas, can regulate apoptosis.

publication date

  • November 2, 2010

has subject area

  • Animals
  • Antigens, CD95
  • Apoptosis
  • Autophagy
  • Caveolin 1
  • Humans
  • Lung
  • Membrane Microdomains
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins
  • Pulmonary Disease, Chronic Obstructive
  • Pulmonary Emphysema
  • Respiratory Mucosa
  • Smoking

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2973911

Digital Object Identifier (DOI)

  • 10.1073/pnas.1005574107

PubMed ID

  • 20956295

Additional Document Info

start page

  • 18880

end page

  • 18885

volume

  • 107

number

  • 44