PSGL-1 and mTOR regulate translation of ROCK-1 and physiological functions of macrophages.
Rho-associated kinases (ROCKs) are critical molecules involved in the physiological functions of macrophages, such as chemotaxis and phagocytosis. We demonstrate that macrophage adherence promotes rapid changes in physiological functions that depend on translational upregulation of preformed ROCK-1 mRNA, but not ROCK-2 mRNA. Before adherence, both ROCK mRNAs were present in the cytoplasm of macrophages, whereas ROCK proteins were undetectable. Macrophage adherence promoted signaling through P-selectin glycoprotein ligand-1 (PSGL-1)/Akt/mTOR that resulted in synthesis of ROCK-1, but not ROCK-2. Following synthesis, ROCK-1 was catalytically active. In addition, there was a rapamycin/sirolimus-sensitive enhanced loading of ribosomes on preformed ROCK-1 mRNAs. Inhibition of mTOR by rapamycin abolished ROCK-1 synthesis in macrophages resulting in an inhibition of chemotaxis and phagocytosis. Macrophages from PSGL-1-deficient mice recapitulated pharmacological inhibitor studies. These results indicate that receptor-mediated regulation at the level of translation is a component of a rapid set of mechanisms required to direct the macrophage phenotype upon adherence and suggest a mechanism for the immunosuppressive and anti-inflammatory effects of rapamycin/sirolimus.
Fox
Richard
R
Department of Pathology, University of Washington, Seattle, WA 98109, USA. richardfox.fox@gmail.com
Nhan
Thomas Q
TQ
Law
G Lynn
GL
Morris
David R
DR
Liles
W Conrad
WC
Schwartz
Stephen M
SM
D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000502:physiology; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D054460:rho-Associated Kinases