Abstract
Patients with primary ovarian insufficiency (POI) often have a high prevalence of autoimmune disorders. To identify antigenic molecules associated with ovarian autoimmunity, we performed immunoprecipitation (IP) screening using serum from patients with POI and the established human granulosa cell line (HGrC1). POTE ankyrin domain family member E (POTEE) and POTE ankyrin domain family member F (POTEF), proteins specific to primates, were identified as candidate antigens. Using immunohistochemistry (IHC) with human ovarian tissue, POTEE or POTEF was weakly seen in the granulosa cells (GCs) of primordial follicles and primary follicles, and strongly in large antral follicles and luteal cells. Interestingly, no signals were detected in growing GCs in secondary, preantral, and small antral follicles. Thus, to explore the function of POTEE and POTEF in human folliculogenesis, we established HGrC1 cell lines with drug-inducible expression of POTEF. Expression of POTEF significantly suppressed cell proliferation in HGrC1 cells. Furthermore, chaperonin containing TCP-1 complex (CCT) components, which affect folding proteins required for cell proliferation, was bound to the actin domain of POTEF protein. Although CCT is normally localized only around the Golgi apparatus, TCP-1α, a component of CCT, co-migrated closer to the cell membrane when POTEF expression was induced. These data suggest that the interaction between POTEF and CCT components impairs the usual function of CCT during cell growth. In addition, over-accumulation of POTEF in HGrC1 cells leads to autophagic failure. It was recently reported that knockout of an autophagic gene in mice leads to a phenotype similar to human POI. These results suggested that a proper amount of POTEF is required for the maintenance of GCs in follicle pools, whereas POTEF overaccumulation might be involved in follicle atresia and the development of POI. We also showed the possibility that POTEF could be an antigen involved in ovarian autoimmunity.
Highlights
Ovarian reserve mainly depends on the number of remaining follicles in the ovary; early depletion of follicles results in primary ovarian insufficiency (POI)
In this study, we identified POTE ankyrin domain family member F (POTEF) and POTE ankyrin domain family member E (POTEE) as candidate proteins contributing to ovarian autoimmunity based on proteomic analysis of IP products in the serum of patients with POI
Using in vitro experiments with a human granulosa cells (GCs) line, we found that POTEF repressed the proliferation of HGrC1 through interactions with the components of chaperonin containing TCP-1 (CCT)
Summary
Ovarian reserve mainly depends on the number of remaining follicles in the ovary; early depletion of follicles results in primary ovarian insufficiency (POI). POI is defined as primary hypogonadism in a woman under the age of 40, mostly diagnosed by the presence of postmenopausal levels of follicle-stimulating hormone (>40 IU/L) in women under 40 years of age after 4 or more months of secondary amenorrhea [1,2,3,4]. POI affects ~1% of women before the age of 40 and 0.1% before the age of 30 [5]. Several lines of evidence currently point toward a link between autoimmunity and POI, including the presence of ovarian autoantibodies such as antibodies against the zona pellucida, oocyte cytoplasm, or entire ovary [11]. Autoantibodies to granulosa cells (GCs) in patients with POI have not been well studied
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