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

Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):E11523-E11531. doi: 10.1073/pnas.1814753115. Epub 2018 Nov 15.


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.

Keywords: Toll-like receptor; inflammation; inflammatory bowel disease; vesicle trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / metabolism
  • Autophagy-Related Proteins
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Colitis / chemically induced
  • Dextran Sulfate
  • Gene Expression Regulation
  • Hematopoiesis / genetics
  • Inflammation / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation
  • Signal Transduction / immunology
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism*


  • Autophagy-Related Proteins
  • C9orf72 Protein
  • C9orf72 protein, mouse
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • SMCR8 protein, mouse
  • Toll-Like Receptors
  • WDR41 protein, mouse
  • Dextran Sulfate