• PMID: 28617811
• Gene Name: GORASP2
• Condition: Spermatogenesis, Male infertility
• Association: Assocaited
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Spermatogenesis, Male infertility

Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis

Cartier-Michaud A, Bailly AL, Betzi S, Shi X, Lissitzky JC, Zarubica A, Sergé A, Roche P, Lugari A, Hamon V, Bardin F, Derviaux C, Lembo F, Audebert S, Marchetto S, Durand B, Borg JP, Shi N, Morelli X, Aurrand-Lions M.

Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes. FAU - Cartier-Michaud, Amandine AU - Cartier-Michaud A AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Bailly, Anne-Laure AU - Bailly AL AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Betzi, Stéphane AU - Betzi S AUID- ORCID: 0000-0001-5935-5058 AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Shi, Xiaoli AU - Shi X AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. AD - State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China. FAU - Lissitzky, Jean-Claude AU - Lissitzky JC AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Zarubica, Ana AU - Zarubica A AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Sergé, Arnauld AU - Sergé A AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Roche, Philippe AU - Roche P AUID- ORCID: 0000-0002-5580-0588 AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Lugari, Adrien AU - Lugari A AUID- ORCID: 0000-0001-8337-6043 AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Hamon, Véronique AU - Hamon V AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Bardin, Florence AU - Bardin F AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Derviaux, Carine AU - Derviaux C AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Lembo, Frédérique AU - Lembo F AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Audebert, Stéphane AU - Audebert S AUID- ORCID: 0000-0002-9409-2588 AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Marchetto, Sylvie AU - Marchetto S AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Durand, Bénédicte AU - Durand B AD - Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Institut NeuroMyoGène, Lyon, France. FAU - Borg, Jean-Paul AU - Borg JP AUID- ORCID: 0000-0001-8418-3382 AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. FAU - Shi, Ning AU - Shi N AUID- ORCID: 0000-0001-8459-3824 AD - State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China. FAU - Morelli, Xavier AU - Morelli X AUID- ORCID: 0000-0001-8101-7901 AD - Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France.