. The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell. 2008 Jun 13;133(6):963-77. PubMed.

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  1. The paper by Tsuda et al. in the latest issue of Cell makes the very interesting suggestion that a Drosophila VAP protein is cleaved, released into the extracellular space, and activates Eph receptors.

    The evidence that the protein is cleaved, or proteolyzed, is based on the immunoblot detection of truncated forms of VAP in wild-type animals and transgenic flies expressing epitope tagged forms of dVAP (dVAP33A). This is consistent with what has previously been shown for the two rodent VAP proteins VAPA and VAPB (1,2). The authors then suggest that a similar truncated form of VAP can be found in human serum. The evidence for this is less compelling. The species detected in human serum is clearly larger than the truncated fragment detected in white blood cells. In addition, this anti-sera was raised to full-length VAPB, and there is no evidence to indicate it is recognizing the MSP domain. It is notable that a number of polyclonal anti-sera raised against full-length recombinant VAPA and VAPB are specific for each protein. Given the near identical structure of the MSP domains, this lack of cross-reactivity may indicate that this domain is poorly immunogenic.

    The presence of dVAP immunoreactivity on the surface of the cell is particularly interesting. Most previous studies have concentrated on VAP proteins present on intracellular membranes such as the ER and Golgi. However, Lapierre et al. (3) have reported that in liver the majority of VAPA was found associated with the plasma membrane, where it interacted with occludin. An important unresolved issue is what proportion of dVAP is actually secreted on the surface, cleaved, or associated with cellular membranes. How the protein gets to the surface of the plasma membrane and out of the cell is yet to be determined. Perhaps it has something to do with the ability of VAP proteins to generate multi-lamella membranes when expressed in certain contexts (4)?

    Interest in VAP proteins was stimulated greatly by the discovery of a familial form of motor neuron disease associated with a missense mutation in VAPB (5). Tsuda et al. demonstrate that the analogous mutation in dVAP, P58S, blocks the delivery of the protein to the surface. Moreover, the mutant protein is shown to associate with the wild-type protein as ubiquitinated aggregates within cells. This is consistent with the mutant protein aggregates described originally and with recent work that reported similar ubiquitinated complexes containing both mutant and wild-type proteins in vertebrate cells (5-7). Similarly, the induction of the unfolded protein response seen in Drosophila overexpressing wild-type or mutant dVAP is consistent with previous findings in vertebrates. However, the exact relationship of VAP proteins with ER stress regulation may be more complicated, as they appear to both increase and reduce different pathways of this regulatory system (1,6,7).

    Whether the protein is cleaved before or after it is secreted is not directly examined. However, since the P58S mutation is retained within cells yet is still cleaved, it seems reasonable to suggest that the cleavage occurs before the MSP domain would be released. How the MSP domain remains associated with the cell membrane in such circumstances is not clear.

    The potential link between Eph receptors and VAP proteins is very exciting. The structure of the MSP domain of VAP proteins and the C. elegans MSP are very similar (8), and the extracellular signaling properties of the Drosophila and human MSP domains expressed in isolation are demonstrated by the ability to mimic C. elegans MSP induced oocyte maturation and sheath contraction. It will be very interesting to see if the C. elegans VAP protein also contributes to the MSP-mediated oocyte maturation process.

    In summary, this report builds upon previous work on the MSPs of C. elegans and on vertebrate and Drosophila VAP proteins, and implicates the Eph/Ephrin pathway in the neurodegenerative processes of motor neuron disease. It also suggests that VAP proteins may be trafficked in cells by previously unappreciated processes. If VAP proteins are shown to have similar properties in vertebrates, then this work may have highlighted a new pathway for therapeutics against motor neuron disease.

    References:

    . VAPB interacts with and modulates the activity of ATF6. Hum Mol Genet. 2008 Jun 1;17(11):1517-26. PubMed.

    . Mouse VAP33 is associated with the endoplasmic reticulum and microtubules. Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1101-6. PubMed.

    . VAP-33 localizes to both an intracellular vesicle population and with occludin at the tight junction. J Cell Sci. 1999 Nov;112 ( Pt 21):3723-32. PubMed.

    . Differential regulation of endoplasmic reticulum structure through VAP-Nir protein interaction. J Biol Chem. 2005 Feb 18;280(7):5934-44. PubMed.

    . A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Nov;75(5):822-31. PubMed.

    . Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). J Biol Chem. 2006 Oct 6;281(40):30223-33. PubMed.

    . Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. J Neurosci. 2007 Sep 5;27(36):9801-15. PubMed.

    . Structural basis of FFAT motif-mediated ER targeting. Structure. 2005 Jul;13(7):1035-45. PubMed.