Marino Zerial

MPI-CBG | Director

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  • Basic Research

    Cell Polarity, homeostasis


    Liver Steatosis

Project Description

The aim of the Zerial group is to elucidate the molecular basis of early endosome structure and function. The group has pioneered the study of small GTPases in endosome transport, with the discovery that Rab5 is an essential component of early endosome biogenesis. By reconstituting Rab5, effectors and SNAREs in synthetic endosomes, it was possible to demonstrate that the Rab5 machinery is necessary for endosome fusion. Silencing Rab5 in mouse liver causes a dramatic depletion of the entire endo-lysosomal system. The function of Rab5 is to regulate the assembly of a multi-protein machinery that confers functional properties to early endosomes, such as specific membrane tethering, fusion and motility. It is now important to understand the molecular mechanism of the Rab5 effectors. For example, the Rab5 effector EEA1 is a tethering molecule. Upon binding, Rab5 induces a change in flexibility of EEA1, generating an entropic collapse force that pulls the captured vesicle towards the target membrane to initiate docking and fusion (Murray, Jahnel et al., Nature 2016).
Work in collaboration with Shashi Thutupalli and Madan Rao at the NCBS aims at analysing the biochemical and physical properties of Rab5 effector recruitment and formation of multi-protein complexes. We are now ready to transfer the knowledge on these biochemical and cellular systems to the scale of tissue organization and function, using the mammalian liver as system. In particular, we are studying the alterations in metabolic (accumulation of lipid droplets), signalling and trafficking (endosomal) pathways in non-alcoholic fatty liver disease (NAFLD).

Fig.: Scheme of Rab5 and its effectors on the early endosome membrane

  • Collection of Lipid Center relevant Publications

    Hsu F, Spannl S, Ferguson C, Hyman AA, Parton RG, Zerial M. Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria. Elife. 2018 Feb 22;7.

    Metzendorf C, Zeigerer A, Seifert S, Sparla R, Najafi B, Canonne-Hergaux F, Zerial M, Muckenthaler MU. Acute loss of the hepatic endo-lysosomal system in vivo causes compensatory changes in iron homeostasis. Sci Rep. 2017 Jun 22;7(1):4023.

    Meyer K, Ostrenko O, Bourantas G, Morales-Navarrete H, Porat-Shliom N, Segovia-Miranda F, Nonaka H, Ghaemi A, Verbavatz JM, Brusch L, Sbalzarini I, Kalaidzidis Y, Weigert R, Zerial M. A Predictive 3D Multi-Scale Model of Biliary Fluid Dynamics in the Liver Lobule. Cell Syst. 2017 Mar 22;4(3):277-290.e9.

    Zeigerer A, Wuttke A, Marsico G, Seifert S, Kalaidzidis Y, Zerial M. Functional properties of hepatocytes in vitro are correlated with cell polarity maintenance. Exp Cell Res. 2017 Jan 1;350(1):242-252.

    Murray DH, Jahnel M, Lauer J, Avellaneda MJ, Brouilly N, Cezanne A, Morales-Navarrete H, Perini ED, Ferguson C, Lupas AN, Kalaidzidis Y, Parton RG, Grill SW, Zerial M. An endosomal tether undergoes an entropic collapse to bring vesicles together. Nature. 2016 Sep 1;537(7618):107-111.

    Villaseñor R, Kalaidzidis Y, Zerial M. Signal processing by the endosomal system. Curr Opin Cell Biol. 2016 Apr;39:53-60.

    Morales-Navarrete H, Segovia-Miranda F, Klukowski P, Meyer K, Nonaka H, Marsico G, Chernykh M, Kalaidzidis A, Zerial M, Kalaidzidis Y. A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3D tissue architecture. Elife. 2015 Dec 27;4.

    Yin H, Bogorad RL, Barnes C, Walsh S, Zhuang I, Nonaka H, Ruda V, Kuchimanchi S, Nechev L, Akinc A, Xue W, Zerial M, Langer R, Anderson DG, Koteliansky V. RNAi-nanoparticulate manipulation of gene expression as a new functional genomics tool in the liver. J Hepatol. 2016 Apr;64(4):899-907.

    Kalaidzidis I, Miaczynska M, Brewińska-Olchowik M, Hupalowska A, Ferguson C, Parton RG, Kalaidzidis Y, Zerial M. APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments. J Cell Biol. 2015 Oct 12;211(1):123-44.

    Gilleron J, Paramasivam P, Zeigerer A, Querbes W, Marsico G, Andree C, Seifert S, Amaya P, Stöter M, Koteliansky V, Waldmann H, Fitzgerald K, Kalaidzidis Y, Akinc A, Maier MA, Manoharan M, Bickle M, Zerial M. Identification of siRNA delivery enhancers by a chemical library screen. Nucleic Acids Res. 2015 Sep 18;43(16):7984-8001. doi: 10.1093/nar/gkv762. Epub 2015 Jul 28. PubMed PMID: 26220182; PubMed Central PMCID: PMC4652771.

    Zeigerer A, Bogorad RL, Sharma K, Gilleron J, Seifert S, Sales S, Berndt N, Bulik S, Marsico G, D’Souza RCJ, Lakshmanaperumal N, Meganathan K, Natarajan K, Sachinidis A, Dahl A, Holzhütter HG, Shevchenko A, Mann M, Koteliansky V, Zerial M. Regulation of liver metabolism by the endosomal GTPase Rab5. Cell Rep. 2015 May 12;11(6):884-892.

    Villaseñor R, Nonaka H, Del Conte-Zerial P, Kalaidzidis Y, Zerial M. Regulation of EGFR signal transduction by analogue-to-digital conversion in endosomes. Elife. 2015 Feb 4;4.