USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma
NATURE MEDICINE
Authors: Eichhorn, Pieter J. A.; Rodon, Laura; Gonzalez-Junca, Alba; Dirac, Annette; Gili, Maguei; Martinez-Saez, Elena; Aura, Claudia; Barba, Ignasi; Peg, Vicente; Prat, Aleix; Cuartas, Isabel; Jimenez, Jose; Garcia-Dorado, David; Sahuquillo, Juan; Bernards, Rene; Baselga, Jose; Seoane, Joan
Abstract
In advanced cancer, including glioblastoma, the transforming growth factor beta (TGF-beta) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-beta signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-beta receptor (T beta R-I), leading to an enhanced TGF-beta signal. High expression of USP15 correlates with high TGF-beta activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-beta activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-beta signaling. Our results show that USP15 regulates the TGF-beta pathway and is a key factor in glioblastoma pathogenesis.
Ubiquitin-Conjugating Enzyme 2S Enhances Viral Replication by Inhibiting Type I IFN Production through Recruiting USP15 to Deubiquitinate TBK1
CELL REPORTS
Authors: Huang, Li; Liu, Hongyang; Zhang, Kunli; Meng, Qingwen; Hu, Liang; Zhang, Yuanfeng; Xiang, Zhida; Li, Jiangnan; Yang, Yuying; Chen, Yali; Cui, Shangjin; Tang, Hong; Pei, Huadong; Bu, Zhigao; Weng, Changjiang
Abstract
Type I interferon (IFN) plays an essential role in the host innate immune responses. Several ubiquitin-conjugating enzyme (E2) family members were reported to regulate type I IFN production and host antiviral immune responses. However, the molecular mechanisms are still not fully understood. Here, we report that UBE2S acts as a negative regulator in the type I IFN signaling pathway. Ectopic expression of UBE2S inhibits host antiviral immune responses and enhances viral replications, whereas deficiency of UBE2S enhances host antiviral immune responses and suppresses viral replications both in vitro and in vivo. Inhibition of type I IFN production by UBE2S is independent on its E2 and E3 enzymic activity. Mechanistically, UBE2S interacts with TBK1 and recruits ubiquitin-specific protease 15 (USP15) to remove Lys63 (K63)-linked polyubiquitin chains of TBK1 Our findings reveal a role of the UBE2S-USP15-TBK1 axis in the regulation of host antiviral innate immune responses.
COA
Publication 
Loading ......
