Trends in Cell Biology
Volume 16, Issue 3, March 2006, Pages 167-173
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The multiple activities of CtBP/BARS proteins: the Golgi view

https://doi.org/10.1016/j.tcb.2006.01.007Get rights and content

The C terminal-binding protein (CtBP) family functions in the nucleus as co-repressors of transcription and has a crucial role in differentiation, apoptosis, oncogenesis and development. Recently, the products of the CtBP1 gene have been implicated in important cytoplasmic functions, including membrane fission in intracellular trafficking, the partitioning of the Golgi complex during mitosis and the organization of ribbon synapses. This has led to a redefinition of the CtBPs as multifunctional proteins. Shuttling of CtBPs between the nucleus and the cytoplasm can be finely regulated by post-translational modifications. In addition, the structural homology with the dehydrogenase family of proteins and the ability of CtBPs to bind NAD+ and acyl-CoAs have offered clues to the molecular mechanisms that enable these proteins to have different functions. Here, we discuss the cytoplasmic roles of the CtBPs and the possible mechanisms that enable them to switch between cell compartments and multiple functions.

Section snippets

The CtBPs, a protein family with multiple cellular functions

The CtBP (C terminal-binding protein) protein family has attracted interest over the past decade because of its many important functions, both in the nucleus as transcriptional co-repressors, and in the cytosol in the control of membrane trafficking. In mammals, the CtBP family is encoded by two genes: CtBP1 and CtBP2. CtBP1 has two splice variants, CtBP1-L (long; previously known as CtBP1) and CtBP1-S/BARS (short; previously known as CtBP3/BARS) (Figure 1) [1]. CtBP2 and RIBEYE are splice

CtBP/BARS membrane fissioning activity

CtBP/BARS was originally identified as a ‘brefeldin A (BFA)-dependent ADP-ribosylation substrate’ during a search for factors that control membrane tubulation 15, 16. BFA is a fungal toxin that promotes the disassembly of the Golgi complex into tubules. Although BFA was known to block the GTP exchange factor for the small GTPase Arf, this did not fully explain the mechanism of the tubular disassembly of the Golgi complex. In a series of studies, it was shown that CtBP/BARS induces the formation

CtBP/BARS-dependent membrane trafficking steps

Intracellular transport involves the formation of vesicular or tubular carriers, which bud and segregate from donor compartments (Box 2, Figure I) 16, 23 and then fuse with an acceptor compartment. Membrane fission is a fundamental event in membrane trafficking.

Increasing evidence suggests that there are several fission machineries in vivo. Many fission events are driven by the proteins of the dynamin family, a versatile and structurally diverse group of large GTPases that can be subdivided

CtBP/BARS mechanism in membrane fission

Although the discovery of the role of CtBP/BARS in membrane fission is relatively recent, a degree of mechanistic understanding of CtBP/BARS has been achieved in a simplified in vitro system that was designed to study the formation of COPI vesicles from washed rat liver Golgi membranes [31]. In the presence of purified Arf, COPI and ARFGAP1, CtBP/BARS is necessary and sufficient for the fission of COPI-coated buds into fully formed vesicles [22]. This effect does not appear to be due to the

Mechanisms of the CtBP/BARS functional switch

CtBP/BARS is localized in the cytoplasm (in the cytosol, at the Golgi complex and at the plasma membrane) and in the nucleus; this is consistent with a dual role in membrane fission and transcriptional regulation [7]. In other proteins that similarly switch between two roles, the change in function is mediated by a change in intracellular location, in oligomerization state, in the binding to different ligands and/or proteins or in post-translational modifications [52]. CtBP1-L shuttles between

Relationships between the nuclear and cytoplasmic functions of CtBP/BARS

Finally, an intriguing area of speculation is whether, and how, the transcriptional and trafficking activities of CtBP/BARS are functionally linked. In some dual-function proteins, such as GAPDH, which is a glycolytic enzyme and a crystallin [61], the different functions are unrelated. In other proteins, the two functions are coordinated and synergistic. For instance, the tumour suppressor p53 [62] translocates to the mitochondria, where it interacts directly with anti-apoptotic proteins,

Future perspectives

The CtBP proteins are well-characterized and functionally important members of the large group of proteins that have different functions in the nucleus and in the cytoplasm 69, 70, 71. Although the separate activities of the CtBPs are being elucidated, the physiological significance of the multifunctional character of these proteins remains relatively unclear and unexplored. However, this might be the most revealing aspect of CtBP biology, as it addresses how the activities of different

Acknowledgements

We thank G. Beznoussenko for providing the tomographic image, R. Gaibisso and A. Spaar for the ribbon diagram representation of CtBP/BARS, A. De Matteis and M. Gimona for critically reading the article, C.P. Berrie for editorial assistance, E. Fontana for preparation of the figures and the Italian Association for Cancer Research (AIRC, Milano, Italy), Telethon Italia (Italy) and the MIUR (Italy) for financial support.

References (77)

  • M. Pagano et al.

    Wagging the dogma; tissue-specific cell cycle control in the mouse embryo

    Cell

    (2004)
  • M. Malumbres

    Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6

    Cell

    (2004)
  • K. Kozar

    Mouse development and cell proliferation in the absence of D-cyclins

    Cell

    (2004)
  • C.J. Jeffery

    Molecular mechanisms for multitasking: recent crystal structures of moonlighting proteins

    Curr. Opin. Struct. Biol.

    (2004)
  • Z.M. Jaffer et al.

    p21-activated kinases: three more join the Pak

    Int. J. Biochem. Cell Biol.

    (2002)
  • X. Lin

    Opposed regulation of corepressor CtBP by SUMOylation and PDZ binding

    Mol. Cell

    (2003)
  • M.H. Kagey

    The polycomb protein Pc2 is a SUMO E3

    Cell

    (2003)
  • J. Rodrigo

    Nitric oxide in the cerebral cortex of amyloid-precursor protein (SW) Tg2576 transgenic mice

    Neuroscience

    (2004)
  • G.M. Riefler et al.

    Binding of neuronal nitric-oxide synthase (nNOS) to carboxyl-terminal-binding protein (CtBP) changes the localization of CtBP from the nucleus to the cytosol: a novel function for targeting by the PDZ domain of nNOS

    J. Biol. Chem.

    (2001)
  • C.J. Jeffery

    Moonlighting proteins

    Trends Biochem. Sci.

    (1999)
  • A.M. Bode et al.

    Targeting signal transduction pathways by chemopreventive agents

    Mutat. Res.

    (2004)
  • X. Brazzolotto

    Structural changes associated with switching activities of human iron regulatory protein 1

    J. Biol. Chem.

    (2002)
  • M.S. Forman

    ‘Unfolding’ pathways in neurodegenerative disease

    Trends Neurosci.

    (2003)
  • D.T. Rutkowski et al.

    A trip to the ER: coping with stress

    Trends Cell Biol.

    (2004)
  • Chinnadurai, G. (2006) CtBP family proteins: unique transcriptional regulators in the nucleus with diverse cytosolic...
  • M. Nardini

    CtBP/BARS: a dual-function protein involved in transcription co-repression and Golgi membrane fission

    EMBO J.

    (2003)
  • S. Spano

    Molecular cloning and functional characterization of brefeldin A-ADP-ribosylated substrate. A novel protein involved in the maintenance of the Golgi structure

    J. Biol. Chem.

    (1999)
  • M. Bonazzi

    CtBP3/BARS drives membrane fission in dynamin-independent transport pathways

    Nat. Cell Biol.

    (2005)
  • S. tom Dieck

    Molecular dissection of the photoreceptor ribbon synapse: physical interaction of Bassoon and RIBEYE is essential for the assembly of the ribbon complex

    J. Cell Biol.

    (2005)
  • Y. Nibu

    dCtBP mediates transcriptional repression by Knirps, Kruppel and Snail in the Drosophila embryo

    EMBO J.

    (1998)
  • G. Poortinga

    Drosophila CtBP: a Hairy-interacting protein required for embryonic segmentation and hairy-mediated transcriptional repression

    EMBO J.

    (1998)
  • U. Folkers

    The cell morphogenesis gene ANGUSTIFOLIA encodes a CtBP/BARS-like protein and is involved in the control of the microtubule cytoskeleton

    EMBO J.

    (2002)
  • G.T. Kim

    The ANGUSTIFOLIA gene of Arabidopsis, a plant CtBP gene, regulates leaf-cell expansion, the arrangement of cortical microtubules in leaf cells and expression of a gene involved in cell-wall formation

    EMBO J.

    (2002)
  • G. Chinnadurai

    CtBP family proteins: more than transcriptional corepressors

    Bioessays

    (2003)
  • Chinnadurai, G., ed. (2006) CtBP Family Proteins, Landes...
  • M.A. De Matteis

    Stimulation of endogenous ADP-ribosylation by brefeldin A

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • D. Corda

    Molecular aspects of membrane fission in the secretory pathway

    Cell. Mol. Life Sci.

    (2002)
  • R. Weigert

    CtBP/BARS induces fission of Golgi membranes by acylating lysophosphatidic acid

    Nature

    (1999)
  • Cited by (0)

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