Preconditioning the uterine unfolded protein response maintains non-apoptotic Caspase 3-dependent quiescence during pregnancy

Judith Ingles,Jennifer C Condon,Chandrashekara Kyathanahalli,Prashanth Anamthathmakula,Sonia Hassan,Arren Simpson,Pancharatnam Jeyasuria

doi:10.1038/s41419-018-1000-4

Abstract

The prevention of apoptotic caspase 3 activation through biological preconditioning, mediated through the modulation of the unfolded protein response has been demonstrated to ameliorate multiple pathophysiologies. The maintenance of non-apoptotic caspase 3 activity by the unfolded protein response within the pregnant uterus has previously been proven to be critical in inhibiting uterine myocyte contractility during pregnancy. Here we report that the pregnant uterus utilizes an unfolded protein response-preconditioning paradigm to conserve myometrial caspase 3 in a non-apoptotic state in order to effectively inhibit uterine contractility thereby preventing the onset of preterm labor. In the absence of appropriate endogenous preconditioning during pregnancy, uterine caspase 3 is transformed from a non-apoptotic to an apoptotic phenotype. Apoptotic caspase 3 activation results in the precocious triggering of local uterine inflammatory signaling and prostaglandin production, consequently resulting in an increased incidence of preterm birth. These findings represent a paradigm shift in our understanding of how preconditioning promotes the maintenance of uterine non-apoptotic caspase 3 action during pregnancy preventing the onset of premature uterine contraction and therefore defining the timing of the onset of labor.

Highlights

Activation of caspase 3 (CASP3) is typically a hallmark of cellular apoptosis or programmed cell death
We have previously demonstrated the critical role the unfolded protein response (UPR) plays in non-apoptotic CASP3 activation within the uterine compartment during pregnancy[1]
The current study is based on the findings that the act of preconditioning the uterine UPR during pregnancy is essential in protecting the pregnant uterine myocyte against a CASP3-mediated apoptotic fate

Summary

Introduction

Activation of caspase 3 (CASP3) is typically a hallmark of cellular apoptosis or programmed cell death. While the tocolytic action of myometrial CASP3 has been highly characterized, it remains elusive as to how the uterus. Ingles et al Cell Death and Disease (2018)9:933 maintaining the tocolytic action of non-apoptotic CASP3, preventing premature uterine contractility. UPR-dependent activation of dna damage inducible transcript 3 (GADD153) has been demonstrated to maintain active non-apoptotic CASP3 at high levels throughout early and mid-gestation[12]. We have shown in the uterus CASP3 inhibits myometrial contraction through the targeted cleavage and degradation of multiple components of the contractile architecture, i.e., connexin 43, α-actin, and γ-actin[1,2]. While the tocolytic function of CASP3 is imminently important, understanding how the pregnant uterus maintains active CASP3 is important and may elucidate novel therapeutic targets for inhibiting preterm labor

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Conclusion