Journal
FASEB JOURNAL
Volume 32, Issue 1, Pages 230-242Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201700415RR
Keywords
deubiquitination; phosphorylation; signal pathway; epithelial barrier integrity
Categories
Funding
- U.S. National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [R01 HL112791, HL131665]
- NIH National Institute of General Medical Sciences [R01GM115389]
- American Lung Association Biomedical Research [RG350146]
- American Heart Association [16GRNT30660001]
Ask authors/readers for more resources
The tumor necrosis factor receptor-associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF-alpha-mediated signaling pathways. Modulation of TRAF2 activity by ubiquitination is well studied; however, the deubiquitinating enzyme (DUB), which regulates TRAF2 stability, has not been identified. Here we reveal USP48 as the first identified DUB to deubiquitinate and stabilize TRAF2 in epithelial cells. Down-regulation of USP48 increases K48-linked polyubiquitination of TRAF2 and reduces TRAF2 protein levels. Interestingly, USP48 only targets the TRAF2 related to JNK pathway, not the TRAF2 related to NF-kappa B and p38 pathways. USP48 is serine phosphorylated in response to TNF-alpha. The phosphorylation is catalyzed by glycogen synthase kinase 3 beta (GSK3 beta), ultimately resulting in increases in USP48 DUB activity. Furthermore, we reveal a new biologic function of TRAF2 that contributes to epithelial barrier dysfunction, which is attenuated by knockdown of USP48. Inhibition of TRAF2/JNK pathway increases E (epithelial)-cadherin expression and enhances epithelial barrier integrity, while knockdown of USP48 attenuates TNF-a/JNK pathway and increases E-cadherin expression and cell-cell junction in epithelial cells. These data, taken together, indicate that USP48 stabilizes TRAF2, which is promoted by GSK3 beta-mediated phosphorylation. Further, down-regulation of USP48 increases E-cadherin expression and epithelial barrier integrity through reducing TRAF2 stability.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available