Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function.
The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72 However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8  mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8  mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8  macrophages. Smcr8  mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand-receptor contact causes inflammatory disease in SMCR8-deficient mice.
['McAlpine|William|W|', 'Sun|Lei|L|', 'Wang|Kuan-Wen|KW|', 'Liu|Aijie|A|', 'Jain|Ruchi|R|', 'San Miguel|Miguel|M|', 'Wang|Jianhui|J|', 'Zhang|Zhao|Z|', 'Hayse|Braden|B|', 'McAlpine|Sarah Grace|SG|', 'Choi|Jin Huk|JH|', 'Zhong|Xue|X|', 'Ludwig|Sara|S|', 'Russell|Jamie|J|', 'Zhan|Xiaoming|X|', 'Choi|Mihwa|M|', 'Li|Xiaohong|X|', 'Tang|Miao|M|', 'Moresco|Eva Marie Y|EMY|', 'Beutler|Bruce|B|0000-0002-3639-246X', 'Turer|Emre|E|']
D000818:Animals D001327:Autoimmune Diseases D000071183:Autophagy-Related Proteins D000073885:C9orf72 Protein D002352:Carrier Proteins D003092:Colitis D016264:Dextran Sulfate D005786:Gene Expression Regulation D006410:Hematopoiesis D007249:Inflammation D047908:Intracellular Signaling Peptides and Proteins D051379:Mice D018345:Mice, Knockout D009154:Mutation D015398:Signal Transduction D051193:Toll-Like Receptors
inflammation Toll-like receptor inflammatory bowel disease vesicle trafficking