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Peer-reviewedCC BYJournal of human immunity

The ups and downs of human UNC93B1: Autoimmune and viral conditions.

  • Elina Idiiatullina1
  • Jean-Laurent Casanova1,2,3,4,5,6,7,8,9
  • Shen-Ying Zhang1,2,3,4,10,11
11 affiliations
  1. 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
  2. 2Laboratory of Human Genetics of Infectious Diseases, Dallas Branch, University of Texas Southwestern, Dallas, TX, USA.
  3. 3Center for the Genetics of Host Defense, The University of Texas Southwestern Medical Center , Dallas, TX, USA.
  4. 4Université Paris Cité, Institut Imagine, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163 , Paris, France.
  5. 5Service de Pédiatrie, AP-HP, Hôpital Necker-Enfants Malades , Paris, France.
  6. 6Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA.
  7. 7Department of Immunology, University of Texas Southwestern, Dallas, TX, USA.
  8. 8Howard Hughes Medical Institute , New York, NY, USA.
  9. 9Children's Hospital Research Institute , Dallas, TX, USA.
  10. 10Department of Neuroscience, University of Texas Southwestern, Dallas, TX, USA.
  11. 11Department of Neurology, University of Texas Southwestern, Dallas, TX, USA.
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Abstract

Mouse Unc93b1 was identified in 2006 by forward genetics as an ER membrane protein essential for the activity of the endosomal nucleic acid-sensing receptors TLR3, TLR7, and TLR9. In vitro studies in mouse and human cells have revealed its cellular functions, including ER-based stabilization and trafficking of endosomal TLR proteins (TLR3, TLR7, TLR8, and TLR9) and regulation of signaling thresholds through competitive trafficking control (TLR7 and TLR9). Human genetic studies have clarified the physiological role of UNC93B1 in natural conditions. Biallelic loss-of-function UNC93B1 mutations impair TLR3 signaling in central nervous system-resident cells, thereby conferring a predisposition to HSV-1 encephalitis. UNC93B1 deficiency may also predispose to other viral infections, as suggested by patients with inherited TLR3 or TLR7 deficiency. Conversely, monoallelic or biallelic UNC93B1 gain-of-function variants enhancing TLR7 and/or TLR8 signaling predispose patients to autoimmunity and inflammation, including early-onset systemic lupus erythematosus and chilblain lupus. Thus, in humans, UNC93B1 maintains a delicate balance between host defense and tolerance to self.

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Cite

BibTeXRIS
BibTeX
@article{idiiatullina2026downs,
  title = {{The ups and downs of human UNC93B1: Autoimmune and viral conditions.}},
  author = {Elina Idiiatullina and Jean-Laurent Casanova and Shen-Ying Zhang},
  journal = {Journal of human immunity},
  year = {2026},
  month = oct,
  doi = {10.70962/jhi.20260059},
  url = {https://europepmc.org/article/MED/42900002},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The ups and downs of human UNC93B1: Autoimmune and viral conditions.
AU  - Elina Idiiatullina
AU  - Jean-Laurent Casanova
AU  - Shen-Ying Zhang
PY  - 2026
DA  - 2026/10/20
JO  - Journal of human immunity
DO  - 10.70962/jhi.20260059
UR  - https://europepmc.org/article/MED/42900002
AB  - Mouse Unc93b1 was identified in 2006 by forward genetics as an ER membrane protein essential for the activity of the endosomal nucleic acid-sensing receptors TLR3, TLR7, and TLR9. In vitro studies in mouse and human cells have revealed its cellular functions, including ER-based stabilization and trafficking of endosomal TLR proteins (TLR3, TLR7, TLR8, and TLR9) and regulation of signaling thresholds through competitive trafficking control (TLR7 and TLR9). Human genetic studies have clarified the physiological role of UNC93B1 in natural conditions. Biallelic loss-of-function UNC93B1 mutations impair TLR3 signaling in central nervous system-resident cells, thereby conferring a predisposition to HSV-1 encephalitis. UNC93B1 deficiency may also predispose to other viral infections, as suggested by patients with inherited TLR3 or TLR7 deficiency. Conversely, monoallelic or biallelic UNC93B1 gain-of-function variants enhancing TLR7 and/or TLR8 signaling predispose patients to autoimmunity and inflammation, including early-onset systemic lupus erythematosus and chilblain lupus. Thus, in humans, UNC93B1 maintains a delicate balance between host defense and tolerance to self.
SN  - 3065-8993
ER  -