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

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90 Citations (Scopus)


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
Publication statusPublished - 2012

Bibliographical note

Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0087610), and by a National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (2010-0017787). E.-W.L. was partly supported by a fellowship from the Brain Korea 21 (BK21) Program.

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy


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