Mapmodulin/Leucine-rich Acidic Nuclear Protein Binds the Light Chain of Microtubule-associated Protein 1B and Modulates Neuritogenesis

We had previously described the leucine-rich acidic nuclear protein (LANP) as a candidate mediator of toxicity in the polyglutamine disease, spinocerebellar ataxia type 1 (SCA1). This was based on the observation that LANP binds ataxin-1, the protein involved in this disease, in a glutamine repeat-dependent manner. Furthermore, LANP is expressed abundantly in purkinje cells, the primary site of ataxin-1 pathology. Here we focused our efforts on understanding the neuronal properties of LANP. In undifferentiated neuronal cells LANP is predominantly a nuclear protein, requiring a bona fide nuclear localization signal to be imported into the nucleus. LANP translocates from the nucleus to the cytoplasm during the process of neuritogenesis, interacts with the light chain of the microtubule-associated protein 1B (MAP1B), and modulates the effects of MAP1B on neurite extension. LANP thus could play a key role in neuronal development and/or neurodegeneration by its interactions with microtubule associated proteins. We had previously described the leucine-rich acidic nuclear protein (LANP) as a candidate mediator of toxicity in the polyglutamine disease, spinocerebellar ataxia type 1 (SCA1). This was based on the observation that LANP binds ataxin-1, the protein involved in this disease, in a glutamine repeat-dependent manner. Furthermore, LANP is expressed abundantly in purkinje cells, the primary site of ataxin-1 pathology. Here we focused our efforts on understanding the neuronal properties of LANP. In undifferentiated neuronal cells LANP is predominantly a nuclear protein, requiring a bona fide nuclear localization signal to be imported into the nucleus. LANP translocates from the nucleus to the cytoplasm during the process of neuritogenesis, interacts with the light chain of the microtubule-associated protein 1B (MAP1B), and modulates the effects of MAP1B on neurite extension. LANP thus could play a key role in neuronal development and/or neurodegeneration by its interactions with microtubule associated proteins. Spinocerebellar ataxia type 1 (SCA1) 1The abbreviations used are: SCA1, spinocerebellar ataxia type 1; LANP, leucine-rich acidic nuclear protein; LRR, leucine-rich repeat; MAP, microtubule-associated protein; HA, hemagglutinin; IP, immunoprecipitation; NLS, nuclear localization signal; DAPI, 4′,6-diamidino-2-phenylindole. belongs to a group of disorders in which a polyglutamine expansion in the disease protein launches a cascade of events that causes relentless neurodegeneration. We had previously proposed that the leucine-rich acidic nuclear protein (LANP) stands out as a particularly appealing candidate mediator of toxicity in SCA1 based on its ability to interact with ataxin-1 in a glutamine repeat-dependent manner (1Matilla A. Koshy B. Cummings C.J. Isobe T. Orr H.T. Zoghbi H.Y. Nature. 1997; 389: 974-978Crossref PubMed Scopus (231) Google Scholar). Moreover, LANP is expressed at particularly high levels in purkinje cells, the seat of SCA1 pathology. Thus, one could envisage a scenario where the functions of LANP could be altered upon binding to ataxin-1, triggering downstream toxic events. This could also account for the regional toxicity of ataxin-1, despite its own ubiquitous expression. Since its first description in 1994, LANP has been implicated in myriad cellular functions from the cell surface to the nucleus. First described as a putative human leukocyte antigen class II-associated protein (and hence called PHAPI), it was suspected to be involved in signal transduction in lymphocytes (2Vaesen M. Barnikol-Watanabe S. Gotz H. Awni L.A. Cole T. Zimmermann B. Kratzin H.D. Hilschmann N. Biol. Chem. Hoppe-Seyler. 1994; 375: 113-126Crossref PubMed Scopus (95) Google Scholar). Matsuoka et al. (1994) independently described this protein in the developing cerebellum, and noting that it contained a leucine-rich repeat, called it by the acronym LANP. With a modular architecture reminiscent of a tadpole, LANP consists of a globular head formed by the N-terminal leucine-rich domain containing five leucine-rich repeats (LRR) and a C-terminal tail formed by the remaining length of acidic residues (3Matsuoka K. Taoka M. Satozawa N. Nakayama H. Ichimura T. Takahashi N. Yamakuni T. Song S.-Y. Isobe T. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9670-9674Crossref PubMed Scopus (75) Google Scholar). As such, it belongs to a large and very interesting family of proteins that contain LRRs crucial for protein interactions, by forming a very characteristic secondary structure designed for protein-protein interactions (4Kobe B. Deisenhofer J. Trends Biochem. Sci. 1994; 19: 415-421Abstract Full Text PDF PubMed Scopus (1047) Google Scholar, 5Kobe B. Deisenhofer J. Nature. 1995; 374: 183-186Crossref PubMed Scopus (576) Google Scholar, 6Kobe B. Deisenhofer J. Curr. Opin. Struct. Biol. 1995; 5: 409-416Crossref PubMed Scopus (322) Google Scholar). It was therefore proposed to be a modulator of signaling pathways in cerebellar morphogenesis. LANP has since been implicated in a number of other functions: as a phosphorylated protein, LANP (known in this context as phosphoprotein 32 or pp32) was suggested to act as tumor suppressor (7Chen T.H. Brody J.R. Romantsev F.E. Yu J.G. Kayler A.E. Voneiff E. Kuhajda F.P. Pasternack G.R. Mol. Biol. 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Since it is unclear which of the functions of LANP, if any, might be perturbed in SCA1 pathogenesis, we sought to understand the neuronal properties of LANP. Here we report that LANP is typically nuclear in undifferentiated neuro2a cells. This compartmentalization is dependent on a nuclear localization signal in its C-terminal domain. LANP tends to be drawn to the cytoplasm during the process of neuronal differentiation. Intriquingly, in a search for LANP interacting proteins, we have identified the microtubule-associated protein, MAP1B, as a cytoplasmic protein that interacts with LANP. This interaction occurs via its light chain. Moreover the effects of MAP1B on neurite extension are altered by its interaction with LANP. This interaction has the potential to not only modulate neuritogenesis during neuronal development, but could also contribute to the loss of neurites and cytoarchitectural disarray seen in SCA1. Yeast Two-hybrid Plasmids and Yeast Strains—Full-length mouse LANP cDNA was subcloned into the NcoI-SmaI sites of the yeast two-hybrid bait and the was into yeast yeast containing the LANP bait were to the yeast with a mouse We used high in and to for interacting were also for in an for the interaction of the bait and interactions the of interaction of LANP we and LANP LANP was by LANP with to the C-terminal acidic the and the the we used a to a LANP into the sites of and from the yeast two-hybrid were subcloned into the of the and containing the chain and of MAP1B at C-terminal to the has been described M. J. Biol. PubMed Scopus Google Scholar). nuclear localization signal of LANP were by a based as to residues and to residues and by into cells were from was used as a neuronal cell of neuro2a cells was by cells in containing L.A. J. PubMed Scopus Google Scholar). on cells, cells or cells of of were neuritogenesis, cells were as neurites if at one process cell in were on the were for M. J. Biol. PubMed Scopus Google Scholar). were by light or were was by with expressed LANP as a protein expressed and into the the light chain of MAP1B to were or and of for and for were at on of and light chain of MAP1B was expressed as an the LANP was expressed as a in cells were with and in of and the in the the or as was with was by protein to and LANP a from the to the upon has been described as a nuclear and a cytoplasmic protein (1Matilla A. Koshy B. Cummings C.J. Isobe T. Orr H.T. Zoghbi H.Y. Nature. 1997; 389: 974-978Crossref PubMed Scopus (231) Google Scholar, 16Ulitzur N. Rancaño C. Pfeffer S.R. J. Biol. Chem. 1997; 272: 30577-30582Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, J. Biol. PubMed Scopus Google Scholar). et al. J. Biol. PubMed Scopus Google Scholar, M. M. M. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) had shown in cells, LANP is a protein that interacts with the nuclear via its leucine-rich of which are for the nuclear seen in and other proteins. it is not to putative nuclear signal the leucine-rich the of the family of proteins B. Deisenhofer J. Curr. Opin. Struct. Biol. 1995; 5: 409-416Crossref PubMed Scopus (322) Google the of based on the ability of to of LANP. LANP also a putative nuclear localization signal in its C-terminal acidic domain. This is a of residues seen in LANP residues In a mouse protein, this to protein is to the nuclear localization of protein that this of as an M. T. T. N. Y. PubMed Scopus Google Scholar). this is the for LANP and residues are for the nuclear localization of LANP, we the and residues of the this to This of LANP called cytoplasmic with type LANP predominantly This also the of LANP to on its type and the nucleus. a scenario might have been based on the ability of LANP to as and as has been previously N. Rancaño C. Pfeffer S.R. J. Biol. Chem. 1997; 272: 30577-30582Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Since LANP is a protein in neuronal cells, with in the we sought to its localization is altered on the process of as has been for other proteins expressed at high levels during development Y. Y. A. H. Full Text PDF PubMed Scopus (64) Google Scholar, T. M. D. D. Res. Mol. Res. 1996; PubMed Scopus Google Scholar). In undifferentiated neuro2a cells, LANP typically is nuclear with cytoplasmic by in the of L.A. J. PubMed Scopus Google LANP tends to be particularly in cells with the neurites In to LANP with an LANP we also LANP into neuro2a cells as to localization by an to the to out the of a in LANP localization from the nucleus to the to the that the nucleus of LANP of undifferentiated cells nuclear upon the a cytoplasmic for LANP. This that LANP from the nucleus to the cytoplasm during neuritogenesis, where its cytoplasmic may be LANP with the neuronal properties of LANP, we to search for LANP interacting proteins expressed in this we a yeast two-hybrid a mouse and LANP as We identified MAP1B as a potential interacting of MAP1B that were out by the two-hybrid are shown in the in to the of the MAP1B We also out to the C-terminal domain of interacting were in This was not in of the that MAP1B and in primary structure in we also identified a number as an interacting Since LANP had been to interact with in biochemical assays we not the interaction of LANP with (15Ulitzur N. Humbert M. Pfeffer S.R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5084-5089Crossref PubMed Scopus (51) Google Scholar, 16Ulitzur N. Rancaño C. Pfeffer S.R. J. Biol. Chem. 1997; 272: 30577-30582Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, C. Ulitzur N. B. Pfeffer S.R. Mol. Biol. Cell. 1999; PubMed Scopus Google Scholar). our microtubule-associated we to the MAP1B interaction as it that LANP has the of binding to of microtubule-associated proteins. MAP1B, with the family of large microtubule-associated proteins. proteins have in to the C-terminal of which contain repeats involved in binding to M. J. Biol. PubMed Scopus Google Scholar, J. J. P. J. Biol. Google Scholar). proteins are also of a to a light chain and a chain 7: Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In the of MAP1B the chain is the light chain is the site has been to residues of a domain of the MAP1B M. 1999; PubMed Scopus Google Scholar). of our to the light chain of MAP1B, residues downstream from the This was the in our yeast two-hybrid interacting with LANP the other MAP1B in the yeast two-hybrid that were or the light chain. This that LANP binds to the light chain Since we were to which domain of LANP the interaction of LANP with MAP1B, we and C-terminal of LANP. yeast two-hybrid assays we were to that the acidic C-terminal domain of LANP with the light chain of MAP1B the N-terminal domain of LANP, the domain the LRRs it is the C-terminal domain that the nuclear localization It be in the context of the domain structure of LANP that it is the N-terminal the leucine-rich that is for the interaction of LANP with ataxin-1 (1Matilla A. Koshy B. Cummings C.J. Isobe T. Orr H.T. Zoghbi H.Y. Nature. 1997; 389: 974-978Crossref PubMed Scopus (231) Google Scholar). LANP with the of MAP1B in Since the of the MAP1B by the yeast two-hybrid to the C-terminal domain of the MAP1B that the light we sought to the that the interaction of LANP is to the light chain of We first to at the localization of LANP in the of the MAP1B light chain LANP predominantly to the nucleus in of the cells. In the of cells in which LANP is the is or as was for cells N. Rancaño C. Pfeffer S.R. J. Biol. Chem. 1997; 272: 30577-30582Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). in our own cells, we that LANP or a nuclear in to the cytoplasmic not with might to the that the used by Ulitzur et al. N. Rancaño C. Pfeffer S.R. J. Biol. Chem. 1997; 272: 30577-30582Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar) only a of LANP in cells based on with the MAP1B light LANP to the cytoplasm in of cells. This to the cytoplasm was and in of the cells LANP tends to be and in a cells the LANP was with MAP1B and LANP, in a This the and microtubule described during on its role in M. J. Biol. PubMed Scopus Google and our own not shown This not only that the light chain of MAP1B interacts with LANP, but that LANP bind at to with the of the MAP1B light chain. In undifferentiated neuro2a cells this to the cytoplasm is with a cytoplasmic of LANP MAP1B light chain is reminiscent of the of LANP seen during the process of differentiation. We sought In we that we the MAP1B light chain to LANP and also in the LANP MAP1B light chain. interaction the is thus to the of LANP for the light chain in cells, we used of MAP1B to the and the chain of MAP1B to mouse and cells with LANP MAP1B or with its chain. We the light chain of MAP1B, MAP1B also causes a of from the nucleus to the with a of cells to a cytoplasmic This was to be since MAP1B is into its and light chain in neuronal and cells and not In the chain causes a from nuclear to cytoplasmic it the number of cells a cytoplasmic from to We that this might be to in the of the light chain by the of it is that is an interaction with the chain as This is since the chain a microtubule binding domain of and to contribute properties to the chain and that could also interact with the acidic tail domain of LANP M. J. Biol. PubMed Scopus Google Scholar). LANP the of MAP1B in that the of light chain to chain is by and of to the light and in a to X. J. Res. 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Sci. 1999; 112: PubMed Google it altered the of neuro2a cells. cells and were of out or neurites with a of neuritogenesis to the light chain the chain had a effects on we that the chain had a on neuritogenesis with the light chain and of cells with the light or were to Thus, it that the light chain and the chain are to the microtubule at the of This on neuritogenesis by MAP1B to LANP modulates the ability of MAP1B to neurite by LANP with MAP1B the ability of the cells to the other LANP not the ability of cells to neurites with the chain or light chain that the on the of neuritogenesis is of its interaction with the MAP1B it is that SCA1 is by an expansion of glutamine repeats in the protein ataxin-1, this expansion into events is an in this were by the that understanding the interactions and functions of proteins that may be by ataxin-1 might to candidate toxic LANP is one ataxin-1 interacting protein that interacts with ataxin-1 its type is expressed at levels in that to be in SCA1, and has been shown to be into ataxin-1 (1Matilla A. 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A. 1997; 94: 5084-5089Crossref PubMed Scopus (51) Google Scholar). are in with a in a cells LANP and MAP1B a that light chain in with the microtubule this acidic domain is by a of proteins, the leucine-rich family or that might also be implicated in functions M. P. PubMed Scopus Google Scholar, H. Y. N. S. K. Biochem. Res. PubMed Scopus Google Scholar). It is an that of this family might have effects on and functions to different cell and LANP, and role of LANP as a modulator of microtubule-associated proteins has for neuronal LANP during at a architecture is in to its role in development, LANP and interaction could also be for the events in SCA1. the had been the and the nuclear events as ataxin-1 We that ataxin-1 binds to LANP in the the interactions of LANP with its cytoplasmic and the of interactions to or in This is not only reminiscent of the in the and disease, where the MAP, tau, is but is also in with the that MAP1B might be involved in the of J. T. P. A. Y. J. 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