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 journalArticlepeer-review

98 Scopus citations


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 (US)
Article number978
JournalNature Communications
StatePublished - 2012

ASJC Scopus subject areas

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


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