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

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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
JournalOncogene
Volume36
Issue number4
DOIs
Publication statusPublished - 2017 Jan 26

Fingerprint

CASP8 and FADD-Like Apoptosis Regulating Protein
Death Domain Receptors
Protein Stability
Ubiquitin
Peptide Hydrolases
Apoptosis
Uterine Cervical Neoplasms
Protein Isoforms
Death Domain Receptor Signaling Adaptor Proteins
Tumor Necrosis Factor-alpha
Receptors, Tumor Necrosis Factor, Type I
Caspase 8
Heterografts
Caspase 3
Melanoma
Neoplasms
Ligands
Cell Line
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Jeong, M., Lee, E. W., Seong, D., Seo, J., Kim, J. H., Grootjans, S., ... Song, J. (2017). USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability. Oncogene, 36(4), 458-470. https://doi.org/10.1038/onc.2016.215
Jeong, M. ; Lee, E. W. ; Seong, D. ; Seo, J. ; Kim, J. H. ; Grootjans, S. ; Kim, S. Y. ; Vandenabeele, P. ; Song, J. / USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability. In: Oncogene. 2017 ; Vol. 36, No. 4. pp. 458-470.
@article{b0130a977fc7408c9a927f005e54ed9f,
title = "USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability",
abstract = "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.",
author = "M. Jeong and Lee, {E. W.} and D. Seong and J. Seo and Kim, {J. H.} and S. Grootjans and Kim, {S. Y.} and P. Vandenabeele and J. Song",
year = "2017",
month = "1",
day = "26",
doi = "10.1038/onc.2016.215",
language = "English",
volume = "36",
pages = "458--470",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "4",

}

Jeong, M, Lee, EW, Seong, D, Seo, J, Kim, JH, Grootjans, S, Kim, SY, Vandenabeele, P & Song, J 2017, 'USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability', Oncogene, vol. 36, no. 4, pp. 458-470. https://doi.org/10.1038/onc.2016.215

USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability. / Jeong, M.; Lee, E. W.; Seong, D.; Seo, J.; Kim, J. H.; Grootjans, S.; Kim, S. Y.; Vandenabeele, P.; Song, J.

In: Oncogene, Vol. 36, No. 4, 26.01.2017, p. 458-470.

Research output: Contribution to journalArticle

TY - JOUR

T1 - USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability

AU - Jeong, M.

AU - Lee, E. W.

AU - Seong, D.

AU - Seo, J.

AU - Kim, J. H.

AU - Grootjans, S.

AU - Kim, S. Y.

AU - Vandenabeele, P.

AU - Song, J.

PY - 2017/1/26

Y1 - 2017/1/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84975302203&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84975302203&partnerID=8YFLogxK

U2 - 10.1038/onc.2016.215

DO - 10.1038/onc.2016.215

M3 - Article

C2 - 27321185

AN - SCOPUS:84975302203

VL - 36

SP - 458

EP - 470

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 4

ER -

Jeong M, Lee EW, Seong D, Seo J, Kim JH, Grootjans S et al. USP8 suppresses death receptor-mediated apoptosis by enhancing FLIP L stability. Oncogene. 2017 Jan 26;36(4):458-470. https://doi.org/10.1038/onc.2016.215