USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPLstability.
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 (FLIPL). USP8 directly deubiquitylates and stabilizes FLIPL, but not the short isoform. USP8 depletion induces FLIPLdestabilization, 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 FLIPLare 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 FLIPLand inhibits extrinsic apoptosis by stabilizing FLIPL.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
M
M
Jeong
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
E-W
EW
Lee
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
D
D
Seong
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
J
J
Seo
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
J-H
JH
Kim
Inflammation Research Center, VIB, Zwijnaarde-Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde-Ghent, Belgium.
S
0000-0002-8385-2545
S
Grootjans
Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Korea.
S-Y
SY
Kim
Inflammation Research Center, VIB, Zwijnaarde-Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde-Ghent, Belgium.
P
0000-0002-6669-8822
P
Vandenabeele
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
J
0000-0001-8152-9210
J
Song
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D056827:Endosomal Sorting Complexes Required for Transport; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase