RRC ID 69976
Author Miyata H, Oura S, Morohoshi A, Shimada K, Mashiko D, Oyama Y, Kaneda Y, Matsumura T, Abbasi F, Ikawa M.
Title SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility in mice.
Journal Proc Natl Acad Sci U S A
Abstract Calcineurin is a calcium-dependent phosphatase that plays roles in a variety of biological processes including immune responses. In spermatozoa, there is a testis-enriched calcineurin composed of PPP3CC and PPP3R2 (sperm calcineurin) that is essential for sperm motility and male fertility. Because sperm calcineurin has been proposed as a target for reversible male contraceptives, identifying proteins that interact with sperm calcineurin widens the choice for developing specific inhibitors. Here, by screening the calcineurin-interacting PxIxIT consensus motif in silico and analyzing the function of candidate proteins through the generation of gene-modified mice, we discovered that SPATA33 interacts with sperm calcineurin via a PQIIIT sequence. Spata33 knockout mice exhibit reduced sperm motility because of an inflexible midpiece, leading to impaired male fertility, which phenocopies Ppp3cc and Ppp3r2 knockout mice. Further analysis reveals that sperm calcineurin disappears from the mitochondria in the Spata33 knockout testis. In addition, immunoprecipitation analysis indicates that sperm calcineurin interacts with not only SPATA33 but also the mitochondrial protein VDAC2. These results indicate that SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility.
Volume 118(35)
Published 2021-8-31
DOI 10.1073/pnas.2106673118
PII 2106673118
PMID 34446558
PMC PMC8536318
MeSH Animals Calcineurin / genetics Calcineurin / metabolism* Female Intercellular Signaling Peptides and Proteins / physiology* Male Mice Mice, Knockout Mitochondria / metabolism* Sperm Motility* Spermatogenesis Testis / physiology* Voltage-Dependent Anion Channel 2 / genetics Voltage-Dependent Anion Channel 2 / metabolism*
IF 9.412
DNA material pCAG-mSpata33-PA (RDB19398) pCAG-mSpata33 (P79A)-PA (RDB19399) pCAG-mSpata33 (I81A)-PA (RDB19400) pCAG-mSpata33 (I83A)-PA (RDB19401) pCAG-hSPATA33-8xHIS-1D4 (RDB19402) pCAG-hPPP3CA-FLAG (RDB19403) pCAG-hPPP3CB-FLAG (RDB19404) pCAG-hPPP3R1 (RDB19405)