Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

Ingrid E. Wertz; Kim Newton; Dhaya Seshasayee; Saritha Kusam; Cynthia Lam; Juan Zhang; Nataliya Popovych; Elizabeth Helgason; Allyn Schoeffler; Surinder Jeet; Nandhini Ramamoorthi; Lorna Kategaya; Robert J. Newman; Keisuke Horikawa; Debra Dugger; Wendy Sandoval; Susmith Mukund; Anuradha Zindal; Flavius Martin; Clifford Quan; Jeffrey Tom; Wayne J. Fairbrother; Michael Townsend; Søren Warming; Jason Devoss; Jinfeng Liu; Erin Dueber; Patrick Caplazi; Wyne P. Lee; Christopher C. Goodnow; Mercedesz Balazs; Kebing Yu; Ganesh Kolumam; Vishva M. Dixit

doi:10.1038/nature16165

Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

Ingrid E. Wertz^*, Kim Newton, Dhaya Seshasayee, Saritha Kusam, Cynthia Lam, Juan Zhang, Nataliya Popovych, Elizabeth Helgason, Allyn Schoeffler, Surinder Jeet, Nandhini Ramamoorthi, Lorna Kategaya, Robert J. Newman, Keisuke Horikawa, Debra Dugger, Wendy Sandoval, Susmith Mukund, Anuradha Zindal, Flavius Martin, Clifford QuanJeffrey Tom, Wayne J. Fairbrother, Michael Townsend, Søren Warming, Jason Devoss, Jinfeng Liu, Erin Dueber, Patrick Caplazi, Wyne P. Lee, Christopher C. Goodnow, Mercedesz Balazs, Kebing Yu, Ganesh Kolumam, Vishva M. Dixit

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

209 Citations (Scopus)

Abstract

Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn € s disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.

Original language	English
Pages (from-to)	370-375
Number of pages	6
Journal	Nature
Volume	528
Issue number	7582
DOIs	https://doi.org/10.1038/nature16165
Publication status	Published - 17 Dec 2015

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Wertz, I. E., Newton, K., Seshasayee, D., Kusam, S., Lam, C., Zhang, J., Popovych, N., Helgason, E., Schoeffler, A., Jeet, S., Ramamoorthi, N., Kategaya, L., Newman, R. J., Horikawa, K., Dugger, D., Sandoval, W., Mukund, S., Zindal, A., Martin, F., ... Dixit, V. M. (2015). Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation. Nature, 528(7582), 370-375. https://doi.org/10.1038/nature16165

@article{def9311c9a98475599a7806c84ea4ed3,

title = "Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation",

abstract = "Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn € s disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.",

author = "Wertz, {Ingrid E.} and Kim Newton and Dhaya Seshasayee and Saritha Kusam and Cynthia Lam and Juan Zhang and Nataliya Popovych and Elizabeth Helgason and Allyn Schoeffler and Surinder Jeet and Nandhini Ramamoorthi and Lorna Kategaya and Newman, {Robert J.} and Keisuke Horikawa and Debra Dugger and Wendy Sandoval and Susmith Mukund and Anuradha Zindal and Flavius Martin and Clifford Quan and Jeffrey Tom and Fairbrother, {Wayne J.} and Michael Townsend and S{\o}ren Warming and Jason Devoss and Jinfeng Liu and Erin Dueber and Patrick Caplazi and Lee, {Wyne P.} and Goodnow, {Christopher C.} and Mercedesz Balazs and Kebing Yu and Ganesh Kolumam and Dixit, {Vishva M.}",

year = "2015",

month = dec,

day = "17",

doi = "10.1038/nature16165",

language = "English",

volume = "528",

pages = "370--375",

journal = "Nature",

issn = "0028-0836",

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Wertz, IE, Newton, K, Seshasayee, D, Kusam, S, Lam, C, Zhang, J, Popovych, N, Helgason, E, Schoeffler, A, Jeet, S, Ramamoorthi, N, Kategaya, L, Newman, RJ, Horikawa, K, Dugger, D, Sandoval, W, Mukund, S, Zindal, A, Martin, F, Quan, C, Tom, J, Fairbrother, WJ, Townsend, M, Warming, S, Devoss, J, Liu, J, Dueber, E, Caplazi, P, Lee, WP, Goodnow, CC, Balazs, M, Yu, K, Kolumam, G & Dixit, VM 2015, 'Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation', Nature, vol. 528, no. 7582, pp. 370-375. https://doi.org/10.1038/nature16165

TY - JOUR

T1 - Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

AU - Wertz, Ingrid E.

AU - Newton, Kim

AU - Seshasayee, Dhaya

AU - Kusam, Saritha

AU - Lam, Cynthia

AU - Zhang, Juan

AU - Popovych, Nataliya

AU - Helgason, Elizabeth

AU - Schoeffler, Allyn

AU - Jeet, Surinder

AU - Ramamoorthi, Nandhini

AU - Kategaya, Lorna

AU - Newman, Robert J.

AU - Horikawa, Keisuke

AU - Dugger, Debra

AU - Sandoval, Wendy

AU - Mukund, Susmith

AU - Zindal, Anuradha

AU - Martin, Flavius

AU - Quan, Clifford

AU - Tom, Jeffrey

AU - Fairbrother, Wayne J.

AU - Townsend, Michael

AU - Warming, Søren

AU - Devoss, Jason

AU - Liu, Jinfeng

AU - Dueber, Erin

AU - Caplazi, Patrick

AU - Lee, Wyne P.

AU - Goodnow, Christopher C.

AU - Balazs, Mercedesz

AU - Yu, Kebing

AU - Kolumam, Ganesh

AU - Dixit, Vishva M.

PY - 2015/12/17

Y1 - 2015/12/17

N2 - Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn € s disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.

AB - Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn € s disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.

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U2 - 10.1038/nature16165

DO - 10.1038/nature16165

M3 - Article

SN - 0028-0836

VL - 528

SP - 370

EP - 375

JO - Nature

JF - Nature

IS - 7582

ER -

Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

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