The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9.
Here we have identified 'triple D' (3d), a recessive N-ethyl-N-nitrosourea-induced mutation and phenotype in which no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 (sensors for double-stranded RNA, single-stranded RNA and unmethylated DNA, respectively). The 3d mutation also prevented cross-presentation and diminished major histocompatibility complex class II presentation of exogenous antigen; it also caused hypersusceptibility to infection by mouse cytomegalovirus and other microbes. By positional identification, we found 3d to be a missense allele of Unc93b1, which encodes the 12-membrane-spanning protein UNC-93B, a highly conserved molecule found in the endoplasmic reticulum with multiple paralogs in mammals. Innate responses to nucleic acids and exogenous antigen presentation, which both initiate in endosomes, thus seem to depend on an endoplasmic reticulum-resident protein, which suggests communication between these organellar systems.
Tabeta
Koichi
K
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Hoebe
Kasper
K
Janssen
Edith M
EM
Du
Xin
X
Georgel
Philippe
P
Crozat
Karine
K
Mudd
Suzanne
S
Mann
Navjiwan
N
Sovath
Sosathya
S
Goode
Jason
J
Shamel
Louis
L
Herskovits
Anat A
AA
Portnoy
Daniel A
DA
Cooke
Michael
M
Tarantino
Lisa M
LM
Wiltshire
Tim
T
Steinberg
Benjamin E
BE
Grinstein
Sergio
S
Beutler
Bruce
B
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D003001:Cloning, Molecular; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007239:Infections / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9