Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection.
Genetic ablation of autophagy in mice leads to liver and brain degeneration accompanied by the appearance of ubiquitin (Ub) inclusions, which has been considered to support the hypothesis that ubiquitination serves as a cis-acting signal for selective autophagy. We show that tissue-specific disruption of the essential autophagy genes Atg5 and Atg7 leads to the accumulation of all detectable Ub-Ub topologies, arguing against the hypothesis that any particular Ub linkage serves as a specific autophagy signal. The increase in Ub conjugates in Atg7(-/-) liver and brain is completely suppressed by simultaneous knockout of either p62 or Nrf2. We exploit a novel assay for selective autophagy in cell culture, which shows that inactivation of Atg5 leads to the selective accumulation of aggregation-prone proteins, and this does not correlate with an increase in substrate ubiquitination. We propose that protein oligomerization drives autophagic substrate selection and that the accumulation of poly-Ub chains in autophagy-deficient circumstances is an indirect consequence of activation of Nrf2-dependent stress response pathways.
Department of Biology, Stanford University, Stanford, CA 94305, USA. brigitriley@gmail.com
Brigit E
BE
Riley
Stephen E
SE
Kaiser
Thomas A
TA
Shaler
Aylwin C Y
AC
Ng
Taichi
T
Hara
Mark S
MS
Hipp
Kasper
K
Lage
Ramnik J
RJ
Xavier
Kwon-Yul
KY
Ryu
Keiko
K
Taguchi
Masayuki
M
Yamamoto
Keiji
K
Tanaka
Noboru
N
Mizushima
Masaaki
M
Komatsu
Ron R
RR
Kopito
D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002478:Cells, Cultured; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011485:Protein Binding; D013312:Stress, Physiological / Q000502:physiology*; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism*
C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D025801:Ubiquitin; D000071193:Autophagy-Related Protein 7