Trends in Cell Biology
The multiple activities of CtBP/BARS proteins: the Golgi view
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.
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