Targeted disruption of tyrosylprotein sulfotransferase-2, an enzyme that catalyzes post-translational protein tyrosine O-sulfation, causes male infertility.
Tyrosine O-sulfation is a post-translational modification mediated by one of two Golgi tyrosylprotein sulfotransferases (TPST-1 and -2) expressed in all mammalian cells. Tyrosine sulfation plays an important role in the function of some known TPST substrates by enhancing protein-protein interactions. To explore the role of these enzymes in vivo and gain insight into other potential TPST substrates, TPST-2-deficient mice were generated by targeted disruption of the Tpst2 gene. Tpst2(+/-) mice appear normal and, when interbred, yield litters of normal size with a Mendelian distribution of the targeted mutation. Tpst2(-/-) mice have moderately delayed growth but appear healthy and attain normal body weight by 10 weeks of age. In contrast to Tpst1(-/-) males that have normal fertility, Tpst2(-/-) males are infertile. Tpst2(-/-) sperm are normal in number, morphology, and motility in normal media and appear to capacitate and undergo acrosomal exocytosis normally. However, they are severely defective in their motility in viscous media and in their ability to fertilize zona pellucida-intact eggs. Adhesion of Tpst2(-/-) sperm to the egg plasma membrane is reduced compared with wild type sperm, but sperm-egg fusion is similar or even increased. These data strongly suggest that tyrosine sulfation of unidentified substrate(s) play a crucial role in these processes and document for the first time the critical importance of post-translational tyrosine sulfation in male fertility.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Atefeh
A
Borghei
Ying-Bin
YB
Ouyang
Andrew D
AD
Westmuckett
Matthew R
MR
Marcello
Carlisle P
CP
Landel
Janice P
JP
Evans
Kevin L
KL
Moore
D000818:Animals; D002448:Cell Adhesion; D006066:Gonads / Q000254:growth & development; D007248:Infertility, Male / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D013081:Sperm Motility; D013091:Spermatogenesis / Q000235:genetics; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D014443:Tyrosine; D015238:Sulfotransferases; C039079:protein-tyrosine sulfotransferase