Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

András N. Spaan; Anna Lena Neehus; Emmanuel Laplantine; Frederik Staels; Masato Ogishi; Yoann Seeleuthner; Franck Rapaport; Keenan A. Lacey; Erika Van Nieuwenhove; Maya Chrabieh; David Hum; Mélanie Migaud; Araksya Izmiryan; Lazaro Lorenzo; Tatiana Kochetkov; Dani A.C. Heesterbeek; Bart W. Bardoel; Ashley L. DuMont; Kerry Dobbs; Solenne Chardonnet; Søren Heissel; Timour Baslan; Peng Zhang; Rui Yang; Dusan Bogunovic; Herman F. Wunderink; Pieter Jan A. Haas; Henrik Molina; Griet Van Buggenhout; Stanislas Lyonnet; Luigi D. Notarangelo; Mikko R.J. Seppänen; Robert Weil; Gisela Seminario; Héctor Gomez-Tello; Carine Wouters; Mehrnaz Mesdaghi; Mohammad Shahrooei; Xavier Bossuyt; Erdal Sag; Rezan Topaloglu; Seza Ozen; Helen L. Leavis; Maarten M.J. van Eijk; Liliana Bezrodnik; Lizbeth Blancas Galicia; Alain Hovnanian; Aude Nassif; Brigitte Bader-Meunier; Bénédicte Neven; Isabelle Meyts; Rik Schrijvers; Anne Puel; Jacinta Bustamante; Ivona Aksentijevich; Daniel L. Kastner; Victor J. Torres; Stéphanie Humblet-Baron; Adrian Liston; Laurent Abel; Bertrand Boisson; Jean Laurent Casanova

doi:10.1126/science.abm6380

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

András N. Spaan, Anna Lena Neehus, Emmanuel Laplantine, Frederik Staels, Masato Ogishi, Yoann Seeleuthner, Franck Rapaport, Keenan A. Lacey, Erika Van Nieuwenhove, Maya Chrabieh, David Hum, Mélanie Migaud, Araksya Izmiryan, Lazaro Lorenzo, Tatiana Kochetkov, Dani A.C. Heesterbeek, Bart W. Bardoel, Ashley L. DuMont, Kerry Dobbs, Solenne ChardonnetSøren Heissel, Timour Baslan, Peng Zhang, Rui Yang, Dusan Bogunovic, Herman F. Wunderink, Pieter Jan A. Haas, Henrik Molina, Griet Van Buggenhout, Stanislas Lyonnet, Luigi D. Notarangelo, Mikko R.J. Seppänen, Robert Weil, Gisela Seminario, Héctor Gomez-Tello, Carine Wouters, Mehrnaz Mesdaghi, Mohammad Shahrooei, Xavier Bossuyt, Erdal Sag, Rezan Topaloglu, Seza Ozen, Helen L. Leavis, Maarten M.J. van Eijk, Liliana Bezrodnik, Lizbeth Blancas Galicia, Alain Hovnanian, Aude Nassif, Brigitte Bader-Meunier, Bénédicte Neven, Isabelle Meyts, Rik Schrijvers, Anne Puel, Jacinta Bustamante, Ivona Aksentijevich, Daniel L. Kastner, Victor J. Torres, Stéphanie Humblet-Baron, Adrian Liston, Laurent Abel, Bertrand Boisson, Jean Laurent Casanova

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Abstract

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor–mediated nuclear factor kB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.

Original language	English
Article number	eabm6380
Journal	Science
Volume	376
Issue number	6599
DOIs	https://doi.org/10.1126/science.abm6380
State	Published - 17 Jun 2022

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Spaan, A. N., Neehus, A. L., Laplantine, E., Staels, F., Ogishi, M., Seeleuthner, Y., Rapaport, F., Lacey, K. A., Van Nieuwenhove, E., Chrabieh, M., Hum, D., Migaud, M., Izmiryan, A., Lorenzo, L., Kochetkov, T., Heesterbeek, D. A. C., Bardoel, B. W., DuMont, A. L., Dobbs, K., ... Casanova, J. L. (2022). Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin. Science, 376(6599), Article eabm6380. https://doi.org/10.1126/science.abm6380

@article{96e2005f25824b3b952341e1ed9be6f6,

title = "Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin",

abstract = "The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor–mediated nuclear factor kB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.",

author = "Spaan, {Andr{\'a}s N.} and Neehus, {Anna Lena} and Emmanuel Laplantine and Frederik Staels and Masato Ogishi and Yoann Seeleuthner and Franck Rapaport and Lacey, {Keenan A.} and {Van Nieuwenhove}, Erika and Maya Chrabieh and David Hum and M{\'e}lanie Migaud and Araksya Izmiryan and Lazaro Lorenzo and Tatiana Kochetkov and Heesterbeek, {Dani A.C.} and Bardoel, {Bart W.} and DuMont, {Ashley L.} and Kerry Dobbs and Solenne Chardonnet and S{\o}ren Heissel and Timour Baslan and Peng Zhang and Rui Yang and Dusan Bogunovic and Wunderink, {Herman F.} and Haas, {Pieter Jan A.} and Henrik Molina and {Van Buggenhout}, Griet and Stanislas Lyonnet and Notarangelo, {Luigi D.} and Sepp{\"a}nen, {Mikko R.J.} and Robert Weil and Gisela Seminario and H{\'e}ctor Gomez-Tello and Carine Wouters and Mehrnaz Mesdaghi and Mohammad Shahrooei and Xavier Bossuyt and Erdal Sag and Rezan Topaloglu and Seza Ozen and Leavis, {Helen L.} and {van Eijk}, {Maarten M.J.} and Liliana Bezrodnik and Galicia, {Lizbeth Blancas} and Alain Hovnanian and Aude Nassif and Brigitte Bader-Meunier and B{\'e}n{\'e}dicte Neven and Isabelle Meyts and Rik Schrijvers and Anne Puel and Jacinta Bustamante and Ivona Aksentijevich and Kastner, {Daniel L.} and Torres, {Victor J.} and St{\'e}phanie Humblet-Baron and Adrian Liston and Laurent Abel and Bertrand Boisson and Casanova, {Jean Laurent}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = jun,

day = "17",

doi = "10.1126/science.abm6380",

language = "English",

volume = "376",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6599",

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Spaan, AN, Neehus, AL, Laplantine, E, Staels, F, Ogishi, M, Seeleuthner, Y, Rapaport, F, Lacey, KA, Van Nieuwenhove, E, Chrabieh, M, Hum, D, Migaud, M, Izmiryan, A, Lorenzo, L, Kochetkov, T, Heesterbeek, DAC, Bardoel, BW, DuMont, AL, Dobbs, K, Chardonnet, S, Heissel, S, Baslan, T, Zhang, P, Yang, R, Bogunovic, D, Wunderink, HF, Haas, PJA, Molina, H, Van Buggenhout, G, Lyonnet, S, Notarangelo, LD, Seppänen, MRJ, Weil, R, Seminario, G, Gomez-Tello, H, Wouters, C, Mesdaghi, M, Shahrooei, M, Bossuyt, X, Sag, E, Topaloglu, R, Ozen, S, Leavis, HL, van Eijk, MMJ, Bezrodnik, L, Galicia, LB, Hovnanian, A, Nassif, A, Bader-Meunier, B, Neven, B, Meyts, I, Schrijvers, R, Puel, A, Bustamante, J, Aksentijevich, I, Kastner, DL, Torres, VJ, Humblet-Baron, S, Liston, A, Abel, L, Boisson, B & Casanova, JL 2022, 'Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin', Science, vol. 376, no. 6599, eabm6380. https://doi.org/10.1126/science.abm6380

TY - JOUR

T1 - Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

AU - Spaan, András N.

AU - Neehus, Anna Lena

AU - Laplantine, Emmanuel

AU - Staels, Frederik

AU - Ogishi, Masato

AU - Seeleuthner, Yoann

AU - Rapaport, Franck

AU - Lacey, Keenan A.

AU - Van Nieuwenhove, Erika

AU - Chrabieh, Maya

AU - Hum, David

AU - Migaud, Mélanie

AU - Izmiryan, Araksya

AU - Lorenzo, Lazaro

AU - Kochetkov, Tatiana

AU - Heesterbeek, Dani A.C.

AU - Bardoel, Bart W.

AU - DuMont, Ashley L.

AU - Dobbs, Kerry

AU - Chardonnet, Solenne

AU - Heissel, Søren

AU - Baslan, Timour

AU - Zhang, Peng

AU - Yang, Rui

AU - Bogunovic, Dusan

AU - Wunderink, Herman F.

AU - Haas, Pieter Jan A.

AU - Molina, Henrik

AU - Van Buggenhout, Griet

AU - Lyonnet, Stanislas

AU - Notarangelo, Luigi D.

AU - Seppänen, Mikko R.J.

AU - Weil, Robert

AU - Seminario, Gisela

AU - Gomez-Tello, Héctor

AU - Wouters, Carine

AU - Mesdaghi, Mehrnaz

AU - Shahrooei, Mohammad

AU - Bossuyt, Xavier

AU - Sag, Erdal

AU - Topaloglu, Rezan

AU - Ozen, Seza

AU - Leavis, Helen L.

AU - van Eijk, Maarten M.J.

AU - Bezrodnik, Liliana

AU - Galicia, Lizbeth Blancas

AU - Hovnanian, Alain

AU - Nassif, Aude

AU - Bader-Meunier, Brigitte

AU - Neven, Bénédicte

AU - Meyts, Isabelle

AU - Schrijvers, Rik

AU - Puel, Anne

AU - Bustamante, Jacinta

AU - Aksentijevich, Ivona

AU - Kastner, Daniel L.

AU - Torres, Victor J.

AU - Humblet-Baron, Stéphanie

AU - Liston, Adrian

AU - Abel, Laurent

AU - Boisson, Bertrand

AU - Casanova, Jean Laurent

PY - 2022/6/17

Y1 - 2022/6/17

N2 - The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor–mediated nuclear factor kB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.

AB - The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor–mediated nuclear factor kB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.

UR - http://www.scopus.com/inward/record.url?scp=85132456095&partnerID=8YFLogxK

U2 - 10.1126/science.abm6380

DO - 10.1126/science.abm6380

M3 - Article

C2 - 35587511

AN - SCOPUS:85132456095

SN - 0036-8075

VL - 376

JO - Science

JF - Science

IS - 6599

M1 - eabm6380

ER -

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

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