Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

Eun Woo Lee, Jung Hoon Kim, Ye Hyeon Ahn, Jinho Seo, Aram Ko, Manhyung Jeong, Seok Jun Kim, Jae Y. Ro, Ki Moon Park, Han Woong Lee, Eun Jung Park, Kyung Hee Chun, Jaewhan Song

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish
Article number978
JournalNature communications
Volume3
DOIs
Publication statusPublished - 2012 Aug 15

Fingerprint

Fas-Associated Death Domain Protein
Death Domain Receptors
Ubiquitination
apoptosis
death
Apoptosis
degradation
proteins
Degradation
Proteins
Death Domain Receptor Signaling Adaptor Proteins
Tumors
rings
Ubiquitin-Protein Ligases
tumors
Caspase 8
Growth
Caspases
Heterografts
Caspase 3

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lee, Eun Woo ; Kim, Jung Hoon ; Ahn, Ye Hyeon ; Seo, Jinho ; Ko, Aram ; Jeong, Manhyung ; Kim, Seok Jun ; Ro, Jae Y. ; Park, Ki Moon ; Lee, Han Woong ; Park, Eun Jung ; Chun, Kyung Hee ; Song, Jaewhan. / Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis. In: Nature communications. 2012 ; Vol. 3.
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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis. / Lee, Eun Woo; Kim, Jung Hoon; Ahn, Ye Hyeon; Seo, Jinho; Ko, Aram; Jeong, Manhyung; Kim, Seok Jun; Ro, Jae Y.; Park, Ki Moon; Lee, Han Woong; Park, Eun Jung; Chun, Kyung Hee; Song, Jaewhan.

In: Nature communications, Vol. 3, 978, 15.08.2012.

Research output: Contribution to journalArticle

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AU - Song, Jaewhan

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