Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function

William McAlpine, Lei Sun, Kuan wen Wang, Aijie Liu, Ruchi Jain, Miguel San Miguel, Jianhui Wang, Zhao Zhang, Braden Hayse, Sarah Grace McAlpine, Jin Huk Choi, Xue Zhong, Sara Ludwig, Jamie L Russell, Xiaoming Zhan, Mihwa Choi, Xiaohong Li, Miao Tang, Eva Marie Y. Moresco, Bruce A BeutlerEmre E Turer

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E11523-E11531
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - Dec 4 2018


  • Inflammation
  • Inflammatory bowel disease
  • Toll-like receptor
  • Vesicle trafficking

ASJC Scopus subject areas

  • General


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