AA28-67 domain within MyD88 suppresses c-myc activity and expression to regulate differentiation and function of dendritic cells.
The mechanism by which c-myc expression in undifferentiated cells rapidly declines following induction of differentiation is poorly characterized. We demonstrate here that MyD88, which can activate NF-kappaB and MAPK, also suppresses c-myc activity and expression. The aa 28-67 domain, a highly conserved region within MyD88, plays a critical role in the MyD88-mediated inhibition. Indeed, deletion of the aa 28-67 domain (MyD88 Delta 28-67) or mutation of the highly conserved amino acid residue phenylalanine (aa 36) to aspartic acid (MyD88 Delta F36D) significantly promoted c-myc activity and expression. Additionally, we found that MyD88 Delta 28-67-mediated c-myc activity and expression could be abrogated using PI3K inhibitor, suggesting that the PI3K/Akt signaling pathway may be involved in MyD88-mediated suppression of c-myc. Compared to MyD88-transduced DCs, MyD88 Delta 28-67- and MyD88 Delta F36D-transduced DCs derived from MyD88-/- bone marrow cells had lower antigen-presenting ability. Thus, MyD88 induces the differentiation and maturation of DCs not only by activating NF-kappaB and MAPK but also via suppressing c-myc activity and expression.
Zhang
Zhuohan
Z
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China.
Zeng
Bin
B
Jiao
Guohui
G
Li
Yuhao
Y
Liu
Yu
Y
Zhang
Yuan
Y
Yang
Rongcun
R
D020816:Amino Acid Motifs; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation; D051379:Mice; D016297:Mutagenesis, Site-Directed; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
C489428:Myc protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D012313:RNA