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 and Jaewhan Song ()
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Eun-Woo Lee: College of Life Science and Biotechnology, Yonsei University
Jung-Hoon Kim: College of Life Science and Biotechnology, Yonsei University
Ye-Hyeon Ahn: College of Life Science and Biotechnology, Yonsei University
Jinho Seo: College of Life Science and Biotechnology, Yonsei University
Aram Ko: College of Life Science and Biotechnology, Yonsei University
Manhyung Jeong: College of Life Science and Biotechnology, Yonsei University
Seok-Jun Kim: Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine
Jae Y. Ro: The Methodist Hospital, Weill Medical College of Cornell University
Ki-Moon Park: Sungkyunkwan University
Han-Woong Lee: College of Life Science and Biotechnology, Yonsei University
Eun Jung Park: Cancer Immunology Branch, National Cancer Center, Goyang
Kyung-Hee Chun: Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine
Jaewhan Song: College of Life Science and Biotechnology, Yonsei University

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1981

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