Methods and compositions for modulating XBP-1 activity
AssigneePresident and Fellows of Harvard College
InventorsLaurie H. Glimcher, Ann-Hwee Lee, Neil Iwakoshi
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Abstract
The invention provides methods and compositions for modulating the expression, processing, post-translational modification, and/or activity of XBP-1 protein, or a protein in a signal transduction pathway involving XBP-1. Exemplary XBP-1 activities that can be modulated using the methods and compositions of the invention include: the Unfolded Protein Response (UPR), plasma cell differentiation, immunoglobulin production, apoptosis and the production of IL-6. The present invention also pertains to methods for identifying compounds that modulate the expression, processing, post-translational modification, and/or activity of XBP-1 protein or a molecule in a signal transduction pathway involving XBP-1.
Claims180
A method of identifying compounds useful in modulating a biological activity of mammalian XBP-1 comprising,
- a) providing an indicator composition comprising mammalian XBP-1 protein;
- b) contacting the indicator composition with each member of a library of test compounds;
- c) selecting from the library of test compounds a compound of interest that modulates the expression, processing, post-translational modification, and/or activity of XBP-1 protein;
- to thereby identify a compound that modulates a biological activity of mammalian XBP-1.
A method of identifying compounds useful in modulating a biological activity of mammalian XBP-1 comprising,
- a) providing an indicator composition comprising mammalian IRE-1 protein;
- b) contacting the indicator composition with each member of a library of test compounds;
- c) selecting from the library of test compounds a compound of interest that modulates the expression, processing, post-translational modification, and/or activity of the IRE-1 protein;
- to thereby identify a compound that modulates a biological activity of mammalian XBP-1.
A method of identifying a compound that modulates a mammalian XBP-1 biological activity comprising:
- a) contacting cells deficient in XBP-1 or a molecule in a signaling pathway involving XBP-1 with a test compound;
- and
- b) determining the effect of the test compound on the XBP-1 biological activity, the test compound being identified as a modulator of the biological activity based on the ability of the test compound to modulate the biological activity in the cells deficient in XBP-1 or a molecule in a signaling pathway involving XBP-1 to thereby identify a compound that modulates a mammalian XBP-1 biological activity.
A method of identifying compounds useful in modulating a biological activity of mammalian XBP-1 comprising:
- a) providing an indicator composition comprising mammalian XBP-1 or a molecule in a signal transduction pathway involving XBP-1;
- b) contacting the indicator composition with each member of a library of test compounds;
- c) selecting from the library of test compounds a compound of interest that modulates the expression, processing, post-translational modification, and/or activity of XBP-1 or the molecule in a signal transduction pathway involving XBP-1;
- to thereby identify a compound that modulates a biological activity of mammalian XBP-1.
A method of identifying a compound useful in modulating an autoimmune disease comprising:
- a) providing an indicator composition comprising mammalian XBP-1 or a molecule in a signal transduction pathway involving XBP-1;
- b) contacting the indicator composition with each member of a library of test compounds;
- c) selecting from the library of test compounds a compound of interest that downmodulates the expression, processing, post-translational modification, and/or activity of XBP-1 or a molecule in a signal transduction pathway involving XBP-1;
- to thereby identify a compound that modulates an autoimmune disease.
A method of identifying a compound useful in treating a malignancy comprising:
- a) providing an indicator composition comprising mammalian XBP-1 or a molecule in a signal transduction pathway involving XBP-1;
- b) contacting the indicator composition with each member of a library of test compounds;
- c) selecting from the library of test compounds a compound of interest that modulates the expression, processing, post-translational modification, and/or activity of XBP-1 or a molecule in a signal transduction pathway involving XBP-1;
- to thereby identify a compound that modulates a malignancy.
A method for identifying a compound which modulates an interaction between mammalian XBP-1 and mammalian IRE-1 comprising:
- (a) providing a first polypeptide comprising a IRE-1 interacting portion of an XBP-1 molecule and a second polypeptide comprising an XBP-1 interacting portion of an IRE-1 molecule in the presence and the absence of a plurality of test compounds;
- and
- (b) determining the degree of interaction between the first and the second polypeptide in the presence and the absence of a test compound to thereby identify a compound which modulates an interaction between mammalian XBP-1 and mammalian IRE-1.
A method for identifying a compound which modulates an interaction between mammalian XBP-1 and mammalian ATF6α comprising:
- (a) providing a first polypeptide comprising a ATF6α interacting portion of an XBP-1 molecule and a second polypeptide comprising an XBP-1 interacting portion of an ATF6oc molecule in the presence and the absence of a plurality of test compounds;
- and
- (b) determining the degree of interaction between the first and the second polypeptide in the presence and the absence of a test compound to thereby identify a compound which modulates an interaction between mammalian XBP-1 and mammalian ATF6α.
A recombinant cell comprising an exogenous mammalian XBP-1 molecule or a portion thereof comprising the nucleotide sequence of XBP-1 spanning the splice junction, and a reporter gene operably linked to a regulatory region responsive to spliced XBP-1 such that upon splicing of the XBP-1 protein, transcription of the reporter gene occurs.
A method for modulating expression and/or activity of mammalian XBP-1 in a cell comprising contacting the cell with an agent that modulates expression and/or activity of a protein that activates XBP-1 to thereby regulate the expression and/or activity of mammalian XBP-1.
A method for modulating expression, in a cell, of a gene whose transcription is regulated by mammalian XBP-1, comprising contacting the cell with an agent that increases expression, processing, post-translational modification, and/or activity of spliced XBP-1 such that expression of the gene is altered.
A method for modulating expression, in a cell, of a gene whose transcription is regulated by mammalian XBP-1, comprising contacting the cell with an agent that increases the ratio of spliced XBP-1 to unspliced XBP-1 such that expression of the gene is altered.
A method for increasing expression, in a mammalian cell, of a gene involved in mediating a biological effect of XBP-1 whose transcription is regulated by XBP-1, comprising contacting a cell with an agent that modulates expression, processing, post-translational modification, and/or activity of XBP-1 in the cell such that expression of the gene is increased.
A method for decreasing expression, in a mammalian cell, of a gene involved in mediating a biological effect of XBP-1 whose transcription is regulated by XBP-1, comprising contacting a cell with an agent that modulates expression, processing, post-translational modification, and/or activity of XBP-1 in the cell such that expression of the gene is decreased.
A method for increasing expression, in a mammalian cell, of a gene involved in mediating a biological effect of XBP-1 whose transcription is regulated by XBP-1, comprising contacting a cell with an agent that increases the activity of spliced XBP-1 in the cell such that expression of the gene is increased.
A method for increasing expression, in a mammalian cell, of a gene involved in mediating a biological effect of XBP-1 whose transcription is regulated by XBP-1, comprising contacting a cell with an agent that decreases the activity of unspliced XBP-1 in the cell such that expression of the gene is increased.
A method for decreasing expression, in a mammalian cell, of a gene involved in mediating a biological effect of XBP-1 whose transcription is regulated by XBP-1, comprising contacting a cell with an agent that decreases the activity of spliced XBP-1 in the cell such that expression of the gene is decreased.
A method for decreasing expression, in a mammalian cell, of a gene involved in mediating a biological effect of XBP-1 whose transcription is regulated by XBP-1, comprising contacting a cell with an agent that increases the activity of unspliced XBP-1 in the cell such that expression of the gene is decreased.
A method of modulating at least one mammalian XBP-1 biological activity comprising contacting a cell with an agent that increases the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in a cell such that at least one biological activity of mammalian XBP-1 is modulated.
A method of modulating at least one mammalian XBP-1 biological activity comprising contacting a cell with an agent that decreases the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in a cell such that the biological activity is modulated.
A method of modulating cellular differentiation comprising contacting a mammalian cell with an agent that increases the expression, processing, post-translational modification, and/or activity of unspliced XBP-1 such that the biological response is modulated.
A method for downmodulating, in mammalian cells, the level of expression of genes which are activated by extracellular influences which induce a signal transduction pathway involving XBP-1, the method comprising contacting a cell with an agent that reduces the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cells such that expression of said genes is reduced.
A method for upmodulating, in mammalian cells, the level of expression of genes which are activated by extracellular influences which induce a signal transduction pathway involving XBP-1, the method comprising contacting a cell with an agent that increases the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cells such that expression of said genes is upmodulated.
A method for downmodulating XBP-1-mediated intracellular signaling in a mammalian cell comprising contacting the cell with an agent that downmodulates the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cell such that XBP-1 mediated intracellular signaling is downmodulated.
A method for upmodulating XBP-1-mediated intracellular signaling comprising contacting a mammalian cell with an agent that upmodulates the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cell such that XBP-1 mediated intracellular signaling is upmodulated.
A method of increasing IL-6 expression in a cell comprising contacting a cell with an agent that increases the activity of spliced XBP-1 in the cell such that IL-6 production is increased.
A method of increasing IL-6 production in a mammalian cell comprising contacting a cell with an agent that decreases the activity of unspliced XBP-1 in the cell such that IL-6 production is increased.
A method of decreasing IL-6 production in a mammalian cell comprising contacting a cell with an agent that decreases the activity of spliced XBP-1 in the cell such that IL-6 production is decreased.
A method of decreasing IL-6 production in a mammalian cell comprising contacting a cell with an agent that increases the activity of unspliced XBP-1 in the cell such that IL-6 production is decreased.
A method of downmodulating apoptosis in a mammalian cell comprising contacting a cell with an agent that increases the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cell such that apoptosis is decreased.
A method of upmodulating apoptosis in a mammalian cell comprising contacting a cell with an agent that decreases the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cell in the cell such that apoptosis is upmodulated.
A method of increasing protein folding, transport, and/or secretion comprising contacting a cell with an agent that increases the expression, processing, post-translational modification, and/or activity of spliced XBP-1 in the cell such that the production of the protein is increased.
A method of increasing protein folding or transport comprising contacting a cell with an agent that decreases the expression, processing, post-translational modification, and/or activity of unspliced XBP-1 in the cell such that production of the protein is increased.
A method of decreasing protein folding or transport in a cell comprising contacting a cell with an agent that increases the expression, processing, post-translational modification, and/or activity of unspliced XBP-1 in the cell such that production of the protein is decreased.
A method of modulating terminal B cell differentiation comprising contacting a mammalian cell with an agent that modulates IL-4 induced signaling in a B cell such that XBP-1 induced transcription is modulated, to thereby modulate terminal B cell differentiation.
A method of modulating an XBP-1 biological activity in a mammalian cell comprising contacting a cell with an agent that induces terminal B cell differentiation.
A method of treating or preventing a disorder that could benefit from treatment with an agent that dowmnodulates the activity of spliced XBP-1 or a molecule in a signal transduction pathway involving XBP-1 in a mammalian subject comprising administering to the subject with said disorder an agent that downmodulates the expression, processing, post-translational modification, and/or activity of XBP-1 or a molecule in a signal transduction pathway involving XBP-1.
A method of treating or preventing a malignancy comprising administering to a mammalian subject with said malignancy an agent that downmodulates the expression, processing, post-translational modification, and/or activity of XBP-1 or a molecule in a signal transduction pathway involving XBP-1 further comprising administering an additional agent useful in treating the malignancy.
A method of treating or preventing a disorder that could benefit from treatment with an agent that upmodulates the activity of spliced XBP-1 or a molecule in a signal transduction pathway involving XBP-1 in a subject comprising administering to the subject with said disorder an agent that upmodulates the expression, processing, post-translational modification, and/or activity of XBP-1 or a molecule in a signal transduction pathway involving XBP-1.
An immunomodulatory composition comprising a nucleic acid molecule encoding spliced mammalian XBP-1 and an antigen.
An immunomodulatory composition comprising a compound that increases spliced mammalian XBP-1 activity and an antigen.
An immunomodulatory composition comprising an inhibitor of spliced mammalian XBP-1 and an antigen.
A method for modulating cellular differentiation in a mammalian subject comprising administering the immunomodulatory compositions of any one of 173-175.
A method for enhancing an immune response in a mammalian subject comprising administering a nucleic acid molecule encoding spliced XBP-1 to the subject such that the immune response is enhanced.
A method of enhancing an immune response in a mammalian subject comprising administering an XBP-1 agonist to the subject such that the immune response is enhanced.
Dependencies are inferred from the claim text.