UNC93B1 variants underlie TLR7-dependent autoimmunity

Christine Wolf; Ee Lyn Lim; Mohammad Mokhtari; Barbara Kind; Alexandru Odainic; Eusebia Lara-Villacanas; Sarah Koss; Simon Mages; Katharina Menzel; Kerstin Engel; Gregor Dückers; Benedikt Bernbeck; Dominik T. Schneider; Kathrin Siepermann; Tim Niehues; Carl Christoph Goetzke; Pawel Durek; Kirsten Minden; Thomas Dörner; Anna Stittrich; Franziska Szelinski; Gabriela Maria Guerra; Mona Massoud; Markus Bieringer; Carina C. de Oliveira Mann; Eduardo Beltrán; Tilmann Kallinich; Mir Farzin Mashreghi; Susanne V. Schmidt; Eicke Latz; Johanna Klughammer; Olivia Majer; Min Ae Lee-Kirsch

doi:10.1126/sciimmunol.adi9769

UNC93B1 variants underlie TLR7-dependent autoimmunity

Christine Wolf, Ee Lyn Lim, Mohammad Mokhtari, Barbara Kind, Alexandru Odainic, Eusebia Lara-Villacanas, Sarah Koss, Simon Mages, Katharina Menzel, Kerstin Engel, Gregor Dückers, Benedikt Bernbeck, Dominik T. Schneider, Kathrin Siepermann, Tim Niehues, Carl Christoph Goetzke, Pawel Durek, Kirsten Minden, Thomas Dörner, Anna StittrichFranziska Szelinski, Gabriela Maria Guerra, Mona Massoud, Markus Bieringer, Carina C. de Oliveira Mann, Eduardo Beltrán, Tilmann Kallinich, Mir Farzin Mashreghi, Susanne V. Schmidt, Eicke Latz, Johanna Klughammer, Olivia Majer, Min Ae Lee-Kirsch

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

16 Scopus citations

Abstract

UNC93B1 is critical for trafficking and function of nucleic acid–sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self–nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype–specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

Original language	English
Article number	eadi9769
Journal	Science Immunology
Volume	9
Issue number	92
DOIs	https://doi.org/10.1126/sciimmunol.adi9769
State	Published - Feb 2024
Externally published	Yes

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Wolf, C., Lim, E. L., Mokhtari, M., Kind, B., Odainic, A., Lara-Villacanas, E., Koss, S., Mages, S., Menzel, K., Engel, K., Dückers, G., Bernbeck, B., Schneider, D. T., Siepermann, K., Niehues, T., Goetzke, C. C., Durek, P., Minden, K., Dörner, T., ... Lee-Kirsch, M. A. (2024). UNC93B1 variants underlie TLR7-dependent autoimmunity. Science Immunology, 9(92), Article eadi9769. https://doi.org/10.1126/sciimmunol.adi9769

@article{feaffef58a9740ccb10253c785f85949,

title = "UNC93B1 variants underlie TLR7-dependent autoimmunity",

abstract = "UNC93B1 is critical for trafficking and function of nucleic acid–sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self–nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype–specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.",

author = "Christine Wolf and Lim, {Ee Lyn} and Mohammad Mokhtari and Barbara Kind and Alexandru Odainic and Eusebia Lara-Villacanas and Sarah Koss and Simon Mages and Katharina Menzel and Kerstin Engel and Gregor D{\"u}ckers and Benedikt Bernbeck and Schneider, {Dominik T.} and Kathrin Siepermann and Tim Niehues and Goetzke, {Carl Christoph} and Pawel Durek and Kirsten Minden and Thomas D{\"o}rner and Anna Stittrich and Franziska Szelinski and Guerra, {Gabriela Maria} and Mona Massoud and Markus Bieringer and {de Oliveira Mann}, {Carina C.} and Eduardo Beltr{\'a}n and Tilmann Kallinich and Mashreghi, {Mir Farzin} and Schmidt, {Susanne V.} and Eicke Latz and Johanna Klughammer and Olivia Majer and Lee-Kirsch, {Min Ae}",

year = "2024",

month = feb,

doi = "10.1126/sciimmunol.adi9769",

language = "English",

volume = "9",

journal = "Science Immunology",

issn = "2470-9468",

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

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Wolf, C, Lim, EL, Mokhtari, M, Kind, B, Odainic, A, Lara-Villacanas, E, Koss, S, Mages, S, Menzel, K, Engel, K, Dückers, G, Bernbeck, B, Schneider, DT, Siepermann, K, Niehues, T, Goetzke, CC, Durek, P, Minden, K, Dörner, T, Stittrich, A, Szelinski, F, Guerra, GM, Massoud, M, Bieringer, M, de Oliveira Mann, CC, Beltrán, E, Kallinich, T, Mashreghi, MF, Schmidt, SV, Latz, E, Klughammer, J, Majer, O & Lee-Kirsch, MA 2024, 'UNC93B1 variants underlie TLR7-dependent autoimmunity', Science Immunology, vol. 9, no. 92, eadi9769. https://doi.org/10.1126/sciimmunol.adi9769

TY - JOUR

T1 - UNC93B1 variants underlie TLR7-dependent autoimmunity

AU - Wolf, Christine

AU - Lim, Ee Lyn

AU - Mokhtari, Mohammad

AU - Kind, Barbara

AU - Odainic, Alexandru

AU - Lara-Villacanas, Eusebia

AU - Koss, Sarah

AU - Mages, Simon

AU - Menzel, Katharina

AU - Engel, Kerstin

AU - Dückers, Gregor

AU - Bernbeck, Benedikt

AU - Schneider, Dominik T.

AU - Siepermann, Kathrin

AU - Niehues, Tim

AU - Goetzke, Carl Christoph

AU - Durek, Pawel

AU - Minden, Kirsten

AU - Dörner, Thomas

AU - Stittrich, Anna

AU - Szelinski, Franziska

AU - Guerra, Gabriela Maria

AU - Massoud, Mona

AU - Bieringer, Markus

AU - de Oliveira Mann, Carina C.

AU - Beltrán, Eduardo

AU - Kallinich, Tilmann

AU - Mashreghi, Mir Farzin

AU - Schmidt, Susanne V.

AU - Latz, Eicke

AU - Klughammer, Johanna

AU - Majer, Olivia

AU - Lee-Kirsch, Min Ae

PY - 2024/2

Y1 - 2024/2

N2 - UNC93B1 is critical for trafficking and function of nucleic acid–sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self–nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype–specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

AB - UNC93B1 is critical for trafficking and function of nucleic acid–sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self–nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype–specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

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U2 - 10.1126/sciimmunol.adi9769

DO - 10.1126/sciimmunol.adi9769

M3 - Article

C2 - 38207055

AN - SCOPUS:85185843289

SN - 2470-9468

VL - 9

JO - Science Immunology

JF - Science Immunology

IS - 92

M1 - eadi9769

ER -

UNC93B1 variants underlie TLR7-dependent autoimmunity

Abstract

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