| RRC ID |
45844
|
| Author |
Safra M, Fickentscher R, Levi-Ferber M, Danino YM, Haviv-Chesner A, Hansen M, Juven-Gershon T, Weiss M, Henis-Korenblit S.
|
| Title |
The FOXO transcription factor DAF-16 bypasses ire-1 requirement to promote endoplasmic reticulum homeostasis.
|
| Journal |
Cell Metab
|
| Abstract |
The unfolded protein response (UPR) allows cells to adjust the capacity of the endoplasmic reticulum (ER) to the load of ER-associated tasks. We show that activation of the Caenorhabditis elegans transcription factor DAF-16 and its human homolog FOXO3 restore secretory protein metabolism when the UPR is dysfunctional.We show that DAF-16 establishes alternative ER-associated degradation systems that degrade misfolded proteins independently of the ER stress sensor ire-1 and the ER-associated E3 ubiquitin ligase complex sel-11/sel-1. This is achieved by enabling autophagy-mediated degradation and by increasing the levels of skr-5, a component of an ER associated ubiquitin ligase complex. These degradation systems can act together with the conserved UPR to improve ER homeostasis and ER stress resistance, beyond wild-type levels. Because there is no sensor in the ER that activates DAF-16 in response to intrinsic ER stress, natural or artificial interventions that activate DAF-16 may be useful therapeutic approaches to maintain ER homeostasis.
|
| Volume |
20(5)
|
| Pages |
870-881
|
| Published |
2014-11-4
|
| DOI |
10.1016/j.cmet.2014.09.006
|
| PII |
S1550-4131(14)00403-3
|
| PMID |
25448701
|
| MeSH |
Animals
Autophagy
Caenorhabditis elegans / cytology*
Caenorhabditis elegans / genetics
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism*
Endoplasmic Reticulum Stress
Endoplasmic Reticulum-Associated Degradation*
Forkhead Box Protein O3
Forkhead Transcription Factors / metabolism*
HEK293 Cells
Humans
Mutation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Unfolded Protein Response
|
| IF |
21.567
|
| Times Cited |
13
|
|
WOS Category
|
ENDOCRINOLOGY & METABOLISM
CELL BIOLOGY
|
| Resource |
| C.elegans |
tm2457 |
