CLIP3 and CYLD bind TNF signaling complex

Stable Identifier
Reaction [binding]
Homo sapiens
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CAP-GLY domain containing linker protein 3 (CLIP3 or CLIPR-59) is thought to function as an adaptor protein recruiting CYLD into the TNFR1 signaling to facilitate CYLD-mediated deubiquitination of RIPK1 in TNFalpha signaling (Fujikura D et al. 2012). CLIP3-assisted CYLD-mediated K63-deubiquitination of RIPK1 may promote caspase-8 activation to induce apoptosis by TNFalpha. The effects of CLIP3 (CLIPR-59) knockdown on apoptosis induction by TNFalpha were more effective in human cervical cancer HeLa cells than in human alveolar basal epithelial A549 cells or human fibrosarcoma HT1080 cells. These findings suggest that the role of CLIP3 on TNF-alpha-induced and RIP1-mediated pro-apoptotic signaling is dependent on cell type and context (Fujikura D et al. 2012). Further, low expression levels of CLIP3 (CLIPR-59) were detected in human glioblastoma multiforme (GBM) cells, such as U87MG, and high grade glioma biopsy samples (Ding Z et al. 2015). In malignant gliomas, a negative relationship between overexpression of speedy protein A (SPDYA or SPY1) and CLIP3 downregulation was associated with a highly aggressive phenotype of glioma (Ding Z et al. 2015; Kang H et al. 2021). In GBM cells, CLIP3 interacted with SPDYA, resulting in decreased association of CLIP3 with CYLD (Ding Z et al. 2015). This in turn led to reduced CYLD-mediated deubiquitination of RIPK1 suppressing TNF-α-induced cell death of glioma cells (Ding Z et al. 2015).

Literature References
PubMed ID Title Journal Year
22435550 Regulation of NF-?B by deubiquitinases

Harhaj, EW, Dixit, VM

Immunol. Rev. 2012
22297296 CLIPR-59 regulates TNF-?-induced apoptosis by controlling ubiquitination of RIP1

Miyazaki, T, Fujikura, D, Reed, JC, Ito, M, Uede, T, Harada, T, Perez, F, Chiba, S

Cell Death Dis 2012
Orthologous Events
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