Oocyte activation and latent HIV-1 reactivation: AMPK as a common mechanism of action linking the beginnings of life and the potential eradication of HIV-1.

摘要: In all mammalian species studied to date, the initiation of oocyte activation is orchestrated through alterations in intracellular calcium (Ca(2+)) signaling. Upon sperm binding plasma membrane, a sperm-associated phospholipase C (PLC) isoform, PLC zeta (PLCζ), released into cytoplasm. PLCζ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) produce diacylglycerol (DAG), which activates protein kinase (PKC), and inositol 1,4,5-trisphosphate (IP3), induces release Ca(2+) from endoplasmic reticulum (ER) stores. Subsequent oscillations are generated that drive completion. ionophores such as ionomycin have been successfully used induce artificial human activation, facilitating fertilization during intra-cytoplasmic injection (ICSI) procedures. Early studies also demonstrated PKC activator phorbol 12-myristate 13-acetate (PMA) acts synergistically with parthenogenetic mouse oocytes. Interestingly, Ca(2+)-induced signaling cascade characterizing or chemically-induced i.e. "shock live" approach, bears striking resemblance reactivation latently infected HIV-1 viral reservoirs via so called kill" method currently being pursued eradicate individuals. PMA combined, positive controls latency reversal studies, shown be extremely efficient reactivating latent CD4(+) memory T cells by inducing cell activation. Similar an increase concentrations DAG, PKC, downstream Ca(2+)-dependent pathways necessary for proviral transcription. AMPK, master regulator metabolism activated thorough induction cellular stress (e.g. concentration, reactive oxygen generation, AMP/ATP ratio) essential maturation, mitochondrial function. addition AMPK LKB1, CaMKK2, Ca(2+)/calmodulin-dependent present on oocytes persists until zygote two-cell stages. It our hypothesis represents central node linking activation-induced both physiological We further propose novel observation various compounds reactivate PMA, ionomycin, metformin, bryostatin, resveratrol, etc.) activate (PMA, ethanol, puromycin, either alone combination likely do stress-induced AMPK.