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

doi:10.1038/ncomms1981

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 journal › Article › peer-review

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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 language	English (US)
Article number	978
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1981
State	Published - 2012

ASJC Scopus subject areas

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

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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.",

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

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.",

year = "2012",

doi = "10.1038/ncomms1981",

language = "English (US)",

volume = "3",

journal = "Nat Commun",

issn = "2041-1723",

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AU - Lee, Eun Woo

AU - Kim, Jung Hoon

AU - Ahn, Ye Hyeon

AU - Seo, Jinho

AU - Ko, Aram

AU - Jeong, Manhyung

AU - Kim, Seok Jun

AU - Ro, Jae Y.

AU - Park, Ki Moon

AU - Lee, Han Woong

AU - Park, Eun Jung

AU - Chun, Kyung Hee

AU - Song, Jaewhan

N1 - 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.

PY - 2012

Y1 - 2012

N2 - 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.

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

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