Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this group, and the most common cause of anovulatory infertility. Although its etiology remains unclear, recent research has revealed the critical role of endoplasmic reticulum (ER) stress in the pathophysiology of PCOS. ER stress is defined as a condition in which unfolded or misfolded proteins accumulate in the ER because of an imbalance in the demand for protein folding and the protein-folding capacity of the ER. ER stress results in the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which regulates various cellular activities. In principle, the UPR restores homeostasis and keeps the cell alive. However, if the ER stress cannot be resolved, it induces programmed cell death. ER stress has recently been recognized to play diverse roles in both physiological and pathological conditions of the ovary. In this review, we summarize current knowledge of the roles of ER stress in the pathogenesis of PCOS. ER stress pathways are activated in the ovaries of both a mouse model of PCOS and in humans, and local hyperandrogenism in the follicular microenvironment associated with PCOS is responsible for activating these. The activation of ER stress contributes to the pathophysiology of PCOS through multiple effects in granulosa cells. Finally, we discuss the potential for ER stress to serve as a novel therapeutic target for PCOS.

Keywords: endoplasmic reticulum stress (ER stress); follicular microenvironment; ovary; pathophysiology; polycystic ovary syndrome (PCOS); unfolded protein response (UPR).

Figure 1

ER stress and the UPR pathway. Under ER stress, three sensor proteins located in the ER membrane are activated. Double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and inositol requiring enzyme 1 (IRE1) are maintained in an inactive state by interaction with the ER chaperone glucose-regulated protein 78 (GRP78), and are activated by dimerization and self-phosphorylation when GRP78 binds to unfolded or misfolded proteins in the ER and is released from PERK and IRE1. PERK phosphorylates eukaryotic initiation factor 2α (eIF2α) that causes translational arrest of most proteins to reduce overload of protein folding in the ER while facilitates translation of activating transcription factor 4 (ATF4). ATF4 induces the transcription of its target genes encoding factors involved in the ER chaperones, amino acid biosynthesis, oxidative stress response and apoptosis. CHOP induced by ATF4 activates apoptotic cascade through the induction of DR5 or Bcl-2-associated X protein (Bax)/Bcl-2 homologous antagonist/killer (Bak). IRE1 is activated by dimerization and self-phosphorylation causing X-box-binding protein 1 (XBP1) mRNA splicing via its endoribonuclease activity. Spliced XBP1 (XBP1s) protein induces transcription of UPR target genes involved in the ER chaperones, ER-associated degradation and cell homeostasis. IRE1 also cleaves ER-associated mRNAs and non-coding functional RNAs, resulting in their degradation through regulated IRE1-dependent decay (RIDD), which reduces protein folding load in the ER or activates apoptotic cascade. IRE1 also binds to adaptor protein, tumor necrosis factor receptor-associated factor 2 (TRAF2), and activates apoptotic cascade through c-Jun N-terminal kinase (JNK) or caspase-12/4 signaling. Activating transcription factor 6 (ATF6) is activated by sequential cleavage in Golgi apparatus, releasing its active fragment, ATF6p50, which induces transcription of UPR target genes involved in the ER chaperones, ER-associated degradation and cell homeostasis.

Figure 2

Functional alteration of GCs induced by ER stress in pathophysiology of PCOS. Molecules involved in the mechanism, either directly or indirectly activated by ER stress, are shown. The number in parentheses refers to the reference number of citation. ER stress is activated in the follicular microenvironment by HA and IR, two key factors underpinning the heterogenous etiology of PCOS. ER stress and the subsequent activation of the UPR contribute to the pathophysiology of PCOS by impairing the function of GCs in multiple ways. ER stress activates the apoptotic cascade in GCs and is associated with follicular growth arrest. The UPR branches, PERK-ATF4-CHOP or IRE1-TRAF2-JNK, induce several caspases-dependent apoptosis. ER stress also induces the ovarian fibrosis that is characteristic of PCOS by increasing the production of profibrotic cytokines, such as TGF-β1 and CTGF, in GCs via the UPR pathway, especially involved in XBP1. ER stress is also associated with high expression of AHR, AHR nuclear translocator (ARNT) and its downstream Cyp1b1 in GCs, which causes alterations in ovarian steroid hormone metabolism. In addition to this, other steroidogenic enzymes, such as Cyp19a1 and Cyp11a1, are induced by the UPR pathway. ER stress also perturbs COC expansion via activation of ATF4 and Notch signaling followed by the induction of ovulation-related genes, such as amphiregulin (Areg), epiregulin (Ereg), hyaluronan synthase 2 (Has2), tumor necrosis factor alpha-induced protein 6 (Tnfaip6) and cyclooxygenase 2 (COX2), in GCs, which might also contribute to the ovulatory dysfunction. ER stress is also associated with the accumulation of AGEs in GCs and an increase in expression of the RAGE through induction of CHOP, resulting in a failure of follicular development. In addition, ER stress in the pancreas, liver, muscle, and adipocytes induces IR and compensatory hyperinsulinemia, which aggravate HA and directly contribute to ovarian dysfunction by impairing PI3K/Akt signaling in GCs. Thus, a vicious circle is formed by HA, hyperinsulinemia, and other proinflammatory factors, and these factors are connected through ER stress.