s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways

Wei Ding; Lorissa J Smulan; Nicole S Hou; Stefan Taubert; Jennifer L Watts; Amy K Walker

doi:10.1016/j.cmet.2015.07.013

s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways

Cell Metab. 2015 Oct 6;22(4):633-45. doi: 10.1016/j.cmet.2015.07.013. Epub 2015 Aug 27.

Authors

Wei Ding¹, Lorissa J Smulan¹, Nicole S Hou², Stefan Taubert², Jennifer L Watts³, Amy K Walker⁴

Affiliations

¹ Program in Molecular Medicine, UMass Worcester, 373 Plantation Street, Worcester, MA 01605, USA.
² Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics (CMMT) and Child & Family Research Institute (CFRI), University of British Columbia (UBC), Vancouver, BC V5Z 4H4, Canada.
³ School of Molecular Biosciences, Washington State University, Pullman, WA 99164-6340, USA.
⁴ Program in Molecular Medicine, UMass Worcester, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: amy.walker@umassmed.edu.

Abstract

s-adenosylmethionine (SAM) is the sole methyl donor modifying histones, nucleic acids, and phospholipids. Its fluctuation affects hepatic phosphatidylcholine (PC) synthesis or may be linked to variations in DNA or histone methylation. Physiologically, low SAM is associated with lipid accumulation, tissue injury, and immune responses in fatty liver disease. However, molecular connections among SAM limitation, methyltransferases, and disease-associated phenotypes are unclear. We find that low SAM can activate or attenuate Caenorhabditis elegans immune responses. Immune pathways are stimulated downstream of PC production on a non-pathogenic diet. In contrast, distinct SAM-dependent mechanisms limit survival on pathogenic Pseudomonas aeruginosa. C. elegans undertakes a broad transcriptional response to pathogens and we find that low SAM restricts H3K4me3 at Pseudomonas-responsive promoters, limiting their expression. Furthermore, this response depends on the H3K4 methyltransferase set-16/MLL. Thus, our studies provide molecular links between SAM and innate immune functions and suggest that SAM depletion may limit stress-induced gene expression.

Publication types

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

MeSH terms

Animals
Caenorhabditis elegans / metabolism
Caenorhabditis elegans / microbiology
Caenorhabditis elegans Proteins / antagonists & inhibitors
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism
Histone Methyltransferases
Histone-Lysine N-Methyltransferase / metabolism
Histones / metabolism
Immunity, Innate*
Liver / metabolism
Methionine Adenosyltransferase / antagonists & inhibitors
Methionine Adenosyltransferase / genetics
Methionine Adenosyltransferase / metabolism
Mitogen-Activated Protein Kinases / metabolism
Phosphatidylcholines / metabolism
Promoter Regions, Genetic
Pseudomonas aeruginosa / physiology
RNA Interference
RNA, Small Interfering / metabolism
S-Adenosylmethionine / metabolism*
Signal Transduction
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Caenorhabditis elegans Proteins
Histones
Phosphatidylcholines
RNA, Small Interfering
S-Adenosylmethionine
Histone Methyltransferases
Histone-Lysine N-Methyltransferase
Methionine Adenosyltransferase
Mitogen-Activated Protein Kinases
Pmk-1 protein, C elegans
p38 Mitogen-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding