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The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E‐cadherin‐mediated adherens junctions
Author(s) -
Li Shuang,
Wang Dan,
Zhao Jing,
Weathington Nathaniel M.,
Shang Dong,
Zhao Yutong
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700415rr
Subject(s) - adherens junction , deubiquitinating enzyme , phosphorylation , traf2 , microbiology and biotechnology , cadherin , ubiquitin , signal transduction , gene knockdown , ubiquitin ligase , catenin , biology , tumor necrosis factor alpha , wnt signaling pathway , cell culture , cell , biochemistry , immunology , gene , genetics , tumor necrosis factor receptor
The tumor necrosis factor receptor‐associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF‐α‐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‐KB and p38 pathways. USP48 is serine phosphorylated in response to TNF‐α. The phosphorylation is catalyzed by glycogen synthase kinase 3β (GSK3β), 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‐α/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 GSK3β‐mediated phosphorylation. Further, down‐regulation of USP48 increases E‐cadherin expression and epithelial barrier integrity through reducing TRAF2 stability.—Li, S., Wang, D., Zhao, J., Weathington, N. M., Shang, D., Zhao, Y. The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E‐cadherin‐mediated adherens junctions. FASEB J. 32,230‐242 (2018). www.fasebj.org