OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin. / Keusekotten, K.; Elliott, P.R.; Kulathu, Y.; Wauer, T.; Hospenthal, M.K.; Komander, D.; Glockner, L.; Krappmann, D.; Fiil, B.K.; Damgaard, R.B.; Gyrd-Hansen, M.; Hofmann, K.

In: Cell, Vol. 153, No. 6, 06.06.2013, p. 1312-1326.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Keusekotten, K, Elliott, PR, Kulathu, Y, Wauer, T, Hospenthal, MK, Komander, D, Glockner, L, Krappmann, D, Fiil, BK, Damgaard, RB, Gyrd-Hansen, M & Hofmann, K 2013, 'OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin', Cell, vol. 153, no. 6, pp. 1312-1326. https://doi.org/10.1016/j.cell.2013.05.014

APA

Keusekotten, K., Elliott, P. R., Kulathu, Y., Wauer, T., Hospenthal, M. K., Komander, D., Glockner, L., Krappmann, D., Fiil, B. K., Damgaard, R. B., Gyrd-Hansen, M., & Hofmann, K. (2013). OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin. Cell, 153(6), 1312-1326. https://doi.org/10.1016/j.cell.2013.05.014

Vancouver

Keusekotten K, Elliott PR, Kulathu Y, Wauer T, Hospenthal MK, Komander D et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin. Cell. 2013 Jun 6;153(6):1312-1326. https://doi.org/10.1016/j.cell.2013.05.014

Author

Keusekotten, K. ; Elliott, P.R. ; Kulathu, Y. ; Wauer, T. ; Hospenthal, M.K. ; Komander, D. ; Glockner, L. ; Krappmann, D. ; Fiil, B.K. ; Damgaard, R.B. ; Gyrd-Hansen, M. ; Hofmann, K. / OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin. In: Cell. 2013 ; Vol. 153, No. 6. pp. 1312-1326.

Bibtex

@article{3cd4a99115a84dd49b74355039d26325,
title = "OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin",
abstract = "The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing k 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling.",
author = "K. Keusekotten and P.R. Elliott and Y. Kulathu and T. Wauer and M.K. Hospenthal and D. Komander and L. Glockner and D. Krappmann and B.K. Fiil and R.B. Damgaard and M. Gyrd-Hansen and K. Hofmann",
year = "2013",
month = jun,
day = "6",
doi = "10.1016/j.cell.2013.05.014",
language = "English",
volume = "153",
pages = "1312--1326",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - OTULIN antagonizes LUBAC signaling by specifically hydrolyzing met1-linked polyubiquitin

AU - Keusekotten, K.

AU - Elliott, P.R.

AU - Kulathu, Y.

AU - Wauer, T.

AU - Hospenthal, M.K.

AU - Komander, D.

AU - Glockner, L.

AU - Krappmann, D.

AU - Fiil, B.K.

AU - Damgaard, R.B.

AU - Gyrd-Hansen, M.

AU - Hofmann, K.

PY - 2013/6/6

Y1 - 2013/6/6

N2 - The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing k 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling.

AB - The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing k 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling.

UR - http://www.scopus.com/inward/record.url?scp=84878862687&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2013.05.014

DO - 10.1016/j.cell.2013.05.014

M3 - Journal article

C2 - 23746843

AN - SCOPUS:84878862687

VL - 153

SP - 1312

EP - 1326

JO - Cell

JF - Cell

SN - 0092-8674

IS - 6

ER -

ID: 46439837