title: Modulation of mutant Huntingtin aggregates and toxicity by human myeloid leukemia factors.
abstract: Increased poly glutamine (polyQ) stretch at N-terminal of Huntingtin (HTT) causes Huntington's disease. HTT interacts with large number of proteins, although the preference for such interactions with wild type or mutated HTT protein remains largely unknown. HYPK, an intrinsically unstructured protein chaperone and interactor of mutant HTT was found to interact with myeloid leukemia factor 1 (MLF1) and 2 (MLF2). To identify the role of these two proteins in mutant HTT mediated aggregate formation and toxicity in a cell model, both the proteins were found to preferentially interact with the mutated N-terminal HTT. They significantly reduced the number of cells containing mutant HTT aggregates and subsequent apoptosis in Neuro2A cells. Additionally, in FRAP assay, mobile fraction of mutant HTT aggregates was increased in the presence of MLF1 or MLF2. Further, MLF1 could release transcription factors like p53, CBP and CREB from mutant HTT aggregates. Moreover, in HeLa cell co-expressing mutant HTT exon1 and full length MLF1, p53 was released from the aggregates, leading to the recovery of the expression of the GADD45A transcript, a p53 regulated gene. Taking together, these results showed that MLF1 and MLF2 modulated the formation of aggregates and induction of apoptosis as well as the expressions of genes indirectly.
authors.affiliation: Crystallography & Molecular Biology Division and Structural Genomics Section, Saha Institute of Nuclear Physics, 1/AF, Bidhan Nagar, Kolkata, 700064, India. Electronic address: manisha.banerjee@gmail.com.
authors.forename: Manisha
authors.initials: M
authors.lastname: Banerjee
authors.affiliation: Crystallography & Molecular Biology Division and Structural Genomics Section, Saha Institute of Nuclear Physics, 1/AF, Bidhan Nagar, Kolkata, 700064, India.
authors.forename: Moumita
authors.initials: M
authors.lastname: Datta
authors.affiliation: Crystallography & Molecular Biology Division and Structural Genomics Section, Saha Institute of Nuclear Physics, 1/AF, Bidhan Nagar, Kolkata, 700064, India. Electronic address: nitai.bhattacharyya@gmail.com.
authors.forename: Nitai P
authors.initials: NP
authors.lastname: Bhattacharyya
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005091:Exons; D036681:Fluorescence Recovery After Photobleaching; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; C100852:MLF1 protein, human; C100853:MLF2 protein, human; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine
keywords: Aggregation; Apoptosis; FRAP; Huntington’s disease; MLF1; MLF2