Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3.
Atg4C/autophagin-3 is a member of a family of cysteine proteinases proposed to be involved in the processing and delipidation of the mammalian orthologues of yeast Atg8, an essential component of an ubiquitin-like modification system required for execution of autophagy. To date, the in vivo role of the different members of this family of proteinases remains unclear. To gain further insights into the functional relevance of Atg4 orthologues, we have generated mutant mice deficient in Atg4C/autophagin-3. These mice are viable and fertile and do not display any obvious abnormalities, indicating that they are able to develop the autophagic response required during the early neonatal period. However, Atg4C-/--starved mice show a decreased autophagic activity in the diaphragm as assessed by immunoblotting studies and by fluorescence microscopic analysis of samples from Atg4C-/- GFP-LC3 transgenic mice. In addition, animals deficient in Atg4C show an increased susceptibility to develop fibrosarcomas induced by chemical carcinogens. Based on these results, we propose that Atg4C is not essential for autophagy development under normal conditions but is required for a proper autophagic response under stressful conditions such as prolonged starvation. We also propose that this enzyme could play an in vivo role in events associated with tumor progression.
Mariño
Guillermo
G
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Salvador-Montoliu
Natalia
N
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Fueyo
Antonio
A
Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Knecht
Erwin
E
Laboratorio de Biologia Celular, Centro de Investigacion Principe Felipe, 46013 Valencia, Spain.
Mizushima
Noboru
N
Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan; Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; SORST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
López-Otín
Carlos
C
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D013997:Time Factors; D014018:Tissue Distribution
D000071183:Autophagy-Related Proteins; C522187:Atg4C protein, mouse; D003546:Cysteine Endopeptidases