LysMD3 is a type II membrane protein without an in vivo role in the response to a range of pathogens

Christine C Yokoyama,Eric Chen,Gaya K Amarasinghe,Vladimir E Diaz-Ochoa,Jacqueline M Kimmey,Kelly M Storek,Guoyan Zhao,Tamara L Doering,Mary C Dinauer,Paul M Allen,Tobias Kerrinnes,Daisy W Leung,Michael N Starnbach,Jeremy P Huynh,Seungmin Hwang,Megan T Baldridge,Caihong Wang,Denise M Monack,Scott A Handley,Sunmin Park,Camaron R Hole,Erica L Sennott,Rachel A Idol,Chandni Desai,Christina L Stallings,Craig A Micchelli,Indira U Mysorekar,Herbert W Virgin,Jonathan Dworkin ,Renée M Tsolis ,Ashley A Viehmann Milam ,Ta‐Chiang Liu

doi:10.1074/jbc.ra117.001246

Abstract

Germline-encoded receptors recognizing common pathogen-associated molecular patterns are a central element of the innate immune system and play an important role in shaping the host response to infection. Many of the innate immune molecules central to these signaling pathways are evolutionarily conserved. LysMD3 is a novel molecule containing a putative peptidoglycan-binding domain that has orthologs in humans, mice, zebrafish, flies, and worms. We found that the lysin motif (LysM) of LysMD3 is likely related to a previously described peptidoglycan-binding LysM found in bacteria. Mouse LysMD3 is a type II integral membrane protein that co-localizes with GM130+ structures, consistent with localization to the Golgi apparatus. We describe here two lines of mLysMD3-deficient mice for in vivo characterization of mLysMD3 function. We found that mLysMD3-deficient mice were born at Mendelian ratios and had no obvious pathological abnormalities. They also exhibited no obvious immune response deficiencies in a number of models of infection and inflammation. mLysMD3-deficient mice exhibited no signs of intestinal dysbiosis by 16S analysis or alterations in intestinal gene expression by RNA sequencing. We conclude that mLysMD3 contains a LysM with cytoplasmic orientation, but we were unable to define a physiological role for the molecule in vivo.

Highlights

Germline-encoded receptors recognizing common pathogenassociated molecular patterns are a central element of the innate immune system and play an important role in shaping the host response to infection
We found that there was no overall difference in M. tuberculosis titers in the lungs of B6, mLysMD3EN/EN, or mLysMD3GT/gene trap (GT) mice at 3 or 13 weeks post-infection (WPI) (Fig. 5, C and D)
We evaluated a possible role for mLysMD3 in the pathogenesis of urinary tract infections (UTIs) caused by the Gramnegative bacterium uropathogenic E. coli (UPEC), which occupies the luminal, intracellular cytoplasmic, and subcellular compartments during infection [32]

Summary

Introduction

Germline-encoded receptors recognizing common pathogenassociated molecular patterns are a central element of the innate immune system and play an important role in shaping the host response to infection. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The innate immune response to infection relies heavily on signals transduced by germline-encoded receptors that recognize common pathogen-associated molecular patterns (PAMPs) such as bacterial and viral proteins, glycoproteins, and microbe-specific nucleic acids [1]. These pattern recognition receptors tend to recognize microbial products that are absent in the host, thereby preventing self-reactivity, are often evolutionarily conserved, and may be members of a protein family that recognize similar but distinct microbial products. Peptidoglycan is a ubiquitous bacterial component, relatively little is known about its interactions with the mammalian immune sys-

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Conclusion