Subcellular Localization Guides eNOS Function

Figures

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  Figure 2. Trafficking and regulation of eNOS in the mitochondria and the nucleus. (1) The expression of eNOS is negatively regulated in the cytosol by eNOS-specific miRNAs. (2) eNOS can be translocated to the outer membrane of the mitochondria in a process that may involve molecular chaperones Hsp90, Hsp70, and CHIP. At this compartment, eNOS can synthesize both O2− and NO, giving rise to peroxynitrite (ONOO−) and nitration and S-nitrosylation of mitochondrial proteins involved in metabolism and bioenergetics. (3 and 4) eNOS can be translocated to the nucleus by binding to the transcription factors ERβ or the complex VEGFR-2-Flk-1/KDR in response to estrogens and VEGF, respectively. (5) NOS-interacting protein (NOSIP) dynamically shuttles between the cytosol and the nuclear compartment, regulating eNOS activity. The nuclear translocation of NOSIP is mediated by transportin 1, a major nuclear import receptor [267]. (6) In the nucleus, eNOS binds to ERβ and hypoxia-induced factor-1 (HIF-1), promoting the transcriptional activity of human telomerase. In this compartment, eNOS also binds and S-nitrosylates ADAR1, which stabilizes double-strand RNA. On the other hand, long non-coding RNAs…

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  Figure 1. Trafficking and regulation of eNOS among the PM, the Golgi, and the cytosol. (1) eNOS associates with caveolin in plasma membrane (PM) caveolae, being activated upon receptor (e.g., GPCR)-induced Ca2+ release from the endoplasmic reticulum (ER) and subsequent binding to Ca2+-Calmodulin (CaM), which dissociates eNOS from caveolin. The activation of eNOS by Ca2+-CaM is stabilized by heat shock protein 90 (Hsp90) and stimulated by L-Arg transporter CAT1 and L-citrulline recyclers argininosuccinate lyase (ASL) and argininosuccinate synthase (ASS), being the soluble guanylate cyclase (sGC) and the production of cGMP as its classical signaling effectors. (2-4) eNOS trafficks from the PM to the Golgi apparatus by acyl protein thioesterase 1 (APT-1)-mediated depalmitoylation and returns to the PM caveolae by DHHC21-mediated repalmitoylation (palmitoylation displayed in blue and myristoylation in red). On the cis-Golgi, eNOS is mainly activated to produce NO by PI3K-Akt-mediated phosphorylation on Cys1177, S-nitrosylating Golgi resident protein transporters such as EMMPRIN and Golgi phosphoprotein 3 (GOLPH3). (5) eNOS binding to NOS-interacting protein (NOSIP) and NOS traffic inducer…