The peptidyl-prolyl isomerase Pin1 regulates granulocyte-macrophage colony-stimulating factor mRNA stability in T lymphocytes.
Cytokine production is associated with both the normal and pathologic inflammatory response to injury. Previous studies have shown that the immunosuppressants cyclosporin A or FK506, which interact with the peptidyl-propyl isomerases cyclophilin A and FK506-binding protein (FKBP12), respectively, block cytokine expression. A third member of the peptidyl-propyl isomerase family, Pin1 is expressed by immune and other cells. Pin1 has been implicated in cell cycle progression, is overexpressed in human tumors, and may rescue neurons from tau-associated degeneration. However, the role of Pin1 in the immune system remains largely unknown. In this study, we analyze the role of Pin1 in GM-CSF expression by human PBMC and CD4+ lymphocytes. We show that Pin1 isomerase activity is necessary for activation-dependent, GM-CSF mRNA stabilization, accumulation, and protein secretion, but not non-AU-rich elements containing cytokine mRNAs, including TGF-beta and IL-4. Mechanistically, Pin1 mediated the association of the AU-rich element-binding protein, AUF1, with GM-CSF mRNA, which determined the rate of decay by the exosome.
Esnault
Stephane
S
Waisman Center for Developmental Disabilities, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine, Madison, WI 53705, USA.
Shen
Zhong-Jian
ZJ
Whitesel
Emily
E
Malter
James S
JS
D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000502:physiology*; D020871:RNA Stability / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism*; D015854:Up-Regulation
D016207:Cytokines; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase