USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability

M. Jeong, E. W. Lee, D. Seong, J. Seo, J. H. Kim, S. Grootjans, S. Y. Kim, P. Vandenabeele, J. Song

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43 Citations (Scopus)


FLICE-like inhibitory protein (FLIP) is a critical regulator of death receptor-mediated apoptosis. Here, we found ubiquitin-specific peptidase 8 (USP8) to be a novel deubiquitylase of the long isoform of FLIP (FLIP L). USP8 directly deubiquitylates and stabilizes FLIP L, but not the short isoform. USP8 depletion induces FLIP L destabilization, promoting anti-Fas-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-and tumor necrosis factor alpha-induced extrinsic apoptosis by facilitating death-inducing signaling complex or TNFR1 complex II formation, which results in the activation of caspase-8 and caspase-3. USP8 mRNA levels are elevated in melanoma and cervical cancers, and the protein levels of USP8 and FLIP L are positively correlated in these cancer cell lines. Xenograft analyses using ME-180 cervical cancer cells showed that USP8 depletion attenuated tumor growth upon TRAIL injection. Taken together, our data indicate that USP8 functions as a novel deubiquitylase of FLIP L and inhibits extrinsic apoptosis by stabilizing FLIP L.

Original languageEnglish
Pages (from-to)458-470
Number of pages13
Issue number4
Publication statusPublished - 2017 Jan 26

Bibliographical note

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research


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