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Cell Mol Life Sci. 2017 Jan;74(2):373-392. doi: 10.1007/s00018-016-2352-5. Epub 2016 Sep 7.

SUMOylation regulates the intracellular fate of ZO-2.

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Institute of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena, Nonnenplan 2-4, 07743, Jena, Germany.
Institut für Ernährungswissenschaften, Abt. Humanernährung, Dornburger Str. 29, 07743, Jena, Germany.
Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (Cinvestav), Mexico City, 07360, Mexico.
Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, CMB Center for Molecular Biomedicine, Hans-Knöll-Str. 2, 07745, Jena, Germany.
Department of Toxicology, University Medical Center Mainz, 55131, Mainz, Germany.
Institute of Physiological Chemistry/Biochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Institute of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena, Nonnenplan 2-4, 07743, Jena, Germany.


The zonula occludens (ZO)-2 protein links tight junctional transmembrane proteins to the actin cytoskeleton and associates with splicing and transcription factors in the nucleus. Multiple posttranslational modifications control the intracellular distribution of ZO-2. Here, we report that ZO-2 is a target of the SUMOylation machinery and provide evidence on how this modification may affect its cellular distribution and function. We show that ZO-2 associates with the E2 SUMO-conjugating enzyme Ubc9 and with SUMO-deconjugating proteases SENP1 and SENP3. In line with this, modification of ZO-2 by endogenous SUMO1 was detectable. Ubc9 fusion-directed SUMOylation confirmed SUMOylation of ZO-2 and was inhibited in the presence of SENP1 but not by an enzymatic-dead SENP1 protein. Moreover, lysine 730 in human ZO-2 was identified as a potential modification site. Mutation of this site to arginine resulted in prolonged nuclear localization of ZO-2 in nuclear recruitment assays. In contrast, a construct mimicking constitutive SUMOylation of ZO-2 (SUMO1ΔGG-ZO-2) was preferentially localized in the cytoplasm. Based on previous findings the differential localization of these ZO-2 constructs may affect glycogen-synthase-kinase-3β (GSK3β) activity and β-catenin/TCF-4-mediated transcription. In this context we observed that ZO-2 directly binds to GSK3β and SUMO1ΔGG-ZO-2 modulates its kinase activity. Moreover, we show that ZO-2 forms a complex with β-catenin. Wild-type ZO-2 and ZO-2-K730R inhibited transcriptional activity in reporter gene assays, whereas the cytosolic SUMO1ΔGG-ZO-2 did not. From these data we conclude that SUMOylation affects the intracellular localization of ZO-2 and its regulatory role on GSK3β and β-catenin signaling activity.


Glycogen-synthase-kinase-3β; Occludin; Tight junction; Zonula occludens-2; β-Catenin

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