Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis.
Developing male germ cells are exquisitely sensitive to environmental insults such as heat and oxidative stress. An additional characteristic of these cells is their unique dependence on RNA-binding proteins for regulating posttranscriptional gene expression and translational control. Here we provide a mechanistic link unifying these two features. We show that the germ cell-specific RNA-binding protein deleted in azoospermia-like (Dazl) is phosphorylated by MAPKAP kinase 2 (MK2), a stress-induced protein kinase activated downstream of p38 MAPK. We demonstrate that phosphorylation of Dazl by MK2 on an evolutionarily conserved serine residue inhibits its interaction with poly(A)-binding protein, resulting in reduced translation of Dazl-regulated target RNAs. We further show that transgenic expression of wild-type human Dazl but not a phosphomimetic form in the Drosophila male germline can restore fertility to flies deficient in boule, the Drosophila orthologue of human Dazl. These results illuminate a novel role for MK2 in spermatogenesis, expand the repertoire of RNA-binding proteins phosphorylated by this kinase, and suggest that signaling by the p38-MK2 pathway is a negative regulator of spermatogenesis via phosphorylation of Dazl.
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.
Patrick A
PA
Williams
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.
Michael S
MS
Krug
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.
Emily A
EA
McMillan
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.
Jasmine D
JD
Peake
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.
Tara L
TL
Davis
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.
Simon
S
Cocklin
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102 Todd.Strochlic@drexelmed.edu.
Todd I
TI
Strochlic
D000818:Animals; D004330:Drosophila / Q000378:metabolism; D015870:Gene Expression; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D000067776:RNA Recognition Motif Proteins; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology; D013737:Testis / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D000067776:RNA Recognition Motif Proteins; D016601:RNA-Binding Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C101358:DAZL protein, human