Estrogen Regulates Microtubule-Associated Protein 1 Light Chain 3 in Mouse Uterine Endometrial Epithelium.

Microtubule-associated protein 1 light chain 3 (LC3) belongs to the ATG8 family and plays a crucial role in regulating the induction of autophagy. Autophagy proceeds via the conversion of LC3B-I to LC3B-II, which is degraded during the fusion of autophagosomes and lysosomes. Uterine autophagy is regulated by ovarian steroid hormones. However, the mechanism governing late-stage autophagic maturation (autophagosome-lysosome fusion) in the uterus remains unclear. We have previously reported that the activity and expression of serine/threonine protein kinase 4 (STK4) are regulated by estrogen (E(2)) in the uterine epithelium. In the present study, we investigated the regulatory role of STK4 in autolysosome formation via LC3. We found that estrogen treatment reduced LC3B-II within three hours, but not LC3B-I, suggesting regulation at the late-stage autophagic maturation step, without evidence of suppressed autophagosome formation. Treatment with the estrogen receptor antagonist ICI 182,780 clearly reversed the reduction in LC3B-II caused by E(2). Furthermore, we discovered that STK4 knockdown decreased the phosphorylation of threonine at the 50th position of the LC3B protein. Finally, we observed that LC3B phosphorylation plays a role in autolysosome formation rather than in autophagosome formation. These findings imply that late-stage autophagic maturation in the uterine epithelium is regulated by LC3B phosphorylation via estrogen and STK4. This will improve our understanding of uterine dynamics via the regulation of autophagy during the estrous cycle.