title: Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis.
abstract: Fas-associated protein with death domain (FADD) is a pivotal component of death receptor-mediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by Makorin Ring Finger Protein 1 (MKRN1) E3 ligase-mediated ubiquitination and proteasomal degradation. MKRN1 knockdown results in FADD protein stabilization and formation of the rapid death-inducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that MKRN1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of MKRN1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using MDA-MB-231 breast cancer cells. Suppression of tumour growth by MKRN1 depletion is relieved by simultaneous FADD knockdown. Our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Eun-Woo
authors.initials: EW
authors.lastname: Lee
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Ye-Hyeon
authors.initials: YH
authors.lastname: Ahn
authors.forename: Jinho
authors.initials: J
authors.lastname: Seo
authors.forename: Aram
authors.initials: A
authors.lastname: Ko
authors.forename: Manhyung
authors.initials: M
authors.lastname: Jeong
authors.forename: Seok-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jae Y
authors.initials: JY
authors.lastname: Ro
authors.forename: Ki-Moon
authors.initials: KM
authors.lastname: Park
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
authors.forename: Jaewhan
authors.initials: J
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D009336:Necrosis / Q000235:genetics / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology*
chemical_list: D053200:Fas-Associated Death Domain Protein; D053218:Receptors, Death Domain