Alternative titles; symbols
HGNC Approved Gene Symbol: ANP32A
Cytogenetic location: 15q23 Genomic coordinates (GRCh38) : 15:68,778,535-68,820,895 (from NCBI)
ANP32A belongs to a family of nuclear proteins implicated in multiple cellular pathways, including transcriptional regulation by chromatin remodeling, mRNA export, and cell death. ANP32 proteins have conserved N-terminal domains containing leucine-rich repeats and C-terminal low-complexity acidic regions rich in glutamic and/or aspartic acid (summary by Long et al., 2016).
The putative HLA class II-associated proteins PHAP I and PHAP II were purified and cloned on the basis of their ability to bind to the cytoplasmic domain of the HLA DR-alpha chain (142860) (Vaesen et al., 1994). They may be components of the transmembrane signaling pathway that is activated after extracellular binding of ligands during the immune response. Both proteins share extensive stretches of highly acidic amino acids in their terminal regions, which suggested a nuclear localization. Indeed, PHAP I is likely to be the human homolog of the rat 'leucine-rich acidic nuclear protein' (LANP) (83.6% identity), which is localized in the nuclei of Purkinje cells. Sequence identity demonstrated that PHAP II is identical to the protein encoded by the gene SET (600960).
Mutation in ataxin-1 (ATX1; 601556) causes spinocerebellar ataxia (SCA1; 164400). Using a yeast 2-hybrid screen of a mouse brain cDNA library with mutant human ATX1 as bait, Matilla et al. (1997) isolated a mouse cDNA encoding Lanp, which is 89% identical to the human protein and is expressed in cerebellum and brainstem. Binding analysis indicated that the strongest interaction between the proteins is with the N-terminal 147 residues on Lanp, which contain 5 leucine-rich repeats, and a full-length ataxin-1 containing 82 glutamines. Immunohistochemical analysis demonstrated highest levels of Lanp, like Atx1, in the nuclei of cerebellar Purkinje cells.
Fink et al. (1995) mapped the PHAP1 gene to 15q22.3-q23 by fluorescence in situ hybridization.
The SET gene is located on 9q34 and was found to be fused to the putative oncogene CAN (114350) in a patient with acute undifferentiated leukemia (von Lindern et al., 1992). The similarities between PHAP I and SET suggested to Fink et al. (1995) that the PHAP1 gene might also form a fusion protein with CAN. In the SET-CAN fusion gene, the breakpoint is located 3-prime of the SET gene, but the last exon of SET is removed in the fusion transcript. This exon encodes the last 7 amino acids (EDEGEDD) of SET that are identical with the end of PHAP I except that PHAP I carries an additional D (EDEGEDDD). The vast majority of cases in which CAN is involved in acute myeloid leukemia show a specificity for the t(6;9) translocation (Sandberg et al., 1983) that fuses the 3-prime part of the CAN gene on 9q34 (von Lindern et al., 1990) to almost the complete coding region of the DEK gene (125264) on 6p23 (von Lindern et al., 1992). The translocation breakpoints always occur in intron icb-9 of CAN. The PHAP1/CAN translocation would be expected to cause acute leukemia. Like DEK and SET, PHAP I contains an extended acidic region that could result in a transforming capacity.
By micropeptide sequence analysis of a PP2A (PPP2CA; 176915) inhibitor and database screening, Li et al. (1996) determined that the inhibitor, termed I1PP2A, was identical to PHAP1. SDS-PAGE analysis indicated that both proteins, which contain 249 amino acids and a highly acidic C-terminal tail, have an apparent molecular mass of 30 kD. Functional analysis showed that recombinant PHAP1 is a potent and specific inhibitor of PP2A and acts by binding to the C subunit of the phosphatase.
Jiang et al. (2003) identified a pathway that regulates mitochondria-initiated caspase activity. In this pathway, PHAP protein promoted caspase-9 (602234) activation after apoptosome formation, whereas PTMA (188390) negatively regulated caspase-9 activation by inhibiting apoptosome formation. A small molecular activator of caspase-3 (600636), PETCM, relieved PTMA inhibition and allowed apoptosome formation at a physiologic concentration of dATP. Elimination of PTMA expression by RNA interference sensitized cells to ultraviolet irradiation-induced apoptosis and negated the requirement of PETCM for caspase activation.
Using a double-knockout approach in 293T cells, Zhang et al. (2019) showed that human ANP32A and ANP32B (619823) were critical host factors that determined influenza virus replication efficiency and subsequent viral production. The 2 proteins functioned independently and contributed equally to virus polymerase activity. Analysis of ANP32A and ANP32B from different species revealed conserved support for influenza A viral replication. However, neither human ANP32A nor ANP32B supported activity of avian viral polymerase, and chicken Anp32b did not support viral RNA replication and left Anp32a alone to support viral replication. Comparison of protein sequences from difference species identified a site between residues 129 to 130 that was vital for influenza polymerase activity in ANP32A and ANP32B. Changes of amino acids in the site resulted in changes in interaction of ANP32A or ANP32B with the viral polymerase complex and influenced influenza virus replication in different species.
Using knockdown analysis in HEK293T cells, Wang et al. (2019) showed that human ANP32A and ANP32B functioned as cellular cofactors required for human immunodeficiency virus (HIV)-1 (see 609423) Gag expression and viral production. ANP32A and ANP32B interacted with Rev, a viral nuclear-cytoplasmic shuttling protein, and enhanced export of unspliced or partially spliced transcripts from the cell nucleus to the cytoplasm. Interaction of ANP32A and ANP32B with Rev was mediated by low complexity acidic region of ANP32 proteins and by the RNA-binding domain of Rev. ANP32A and ANP32B also interacted and cooperated with CRM1 (XPO1; 602559) to support Rev-dependent nuclear export of unspliced or partially spliced HIV-1 RNA to the cytoplasm. Although ANP32A and ANP32B interacted with both Rev and CRM1, they did not disrupt Rev-CRM1 interaction.
Using a chicken-hamster radiation hybrid panel, followed by expression of candidate genes in a human embryonic kidney cell line, Long et al. (2016) found that expression of chicken Anp32a, but not chicken Ddx17 (608469) or importin-alpha family members (e.g., KPNA2; 600685), rescued avian influenza virus polymerase activity in human cells. Human ANP32A and ANP32B (619823) failed to permit avian, but not human, influenza activity. Knockdown of Anp32a in chicken cells decreased the yield of infectious influenza virus. Sequence analysis revealed that avian (except ratite, a flightless bird) Anp32a harbors an additional 33 amino acids, derived from a partial repeat of residues 149 to 175, encoded by an additional exon that is absent in mammals and ostriches. Several avian forms of Anp32a, but not ostrich or mammalian Anp32a, increased avian, but not human-adapted, influenza virus polymerase activity. Deletion of amino acids 176 to 208 of chicken Anp32a abrogated support of the avian virus polymerase. Long et al. (2016) proposed that avian influenza virus has coevolved with its natural hosts to coopt avian Anp32a as a host factor that supports its polymerase activity in nucleus, whereas the shorter mammalian forms of ANP32A, including human, do not support this activity.
Fink, T. M., Vaesen, M., Kratzin, H. D., Lichter, P., Zimmer, M. Localization of the gene encoding the putative human HLA class II associated protein (PHAPI) to chromosome 15q22.3-q23 by fluorescence in situ hybridization. Genomics 29: 309-310, 1995. [PubMed: 8530098] [Full Text: https://doi.org/10.1006/geno.1995.1257]
Jiang, X., Kim, H.-E., Shu, H., Zhao, Y., Zhang, H., Kofron, J., Donnelly, J., Burns, D., Ng, S., Rosenberg, S., Wang, X. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science 299: 223-226, 2003. [PubMed: 12522243] [Full Text: https://doi.org/10.1126/science.1076807]
Li, M., Makkinje, A., Damuni, Z. Molecular identification of I-1(PP2A), a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry 35: 6998-7002, 1996. [PubMed: 8679524] [Full Text: https://doi.org/10.1021/bi960581y]
Long, J. S., Giotis, E. S., Moncorge, O., Frise, R., Mistry, B., James, J., Morisson, M., Iqbal, M., Vignal, A., Skinner, M. A., Barclay, W. S. Species difference in ANP32A underlies influenza A virus polymerase host restriction. Nature 529: 101-104, 2016. [PubMed: 26738596] [Full Text: https://doi.org/10.1038/nature16474]
Matilla, A., Koshy, B. T., Cummings, C. J., Isobe, T., Orr, H. T., Zoghbi, H. Y. The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389: 974-978, 1997. Note: Erratum: Nature 391: 818 only, 1998. [PubMed: 9353121] [Full Text: https://doi.org/10.1038/40159]
Sandberg, A. A., Morgan, R., McCallister, J. A., Kaiser-McCaw, B., Hecht, F. Acute myeloblastic leukemia (AML) with t(6;9)(p23;q34): a specific subgroup of AML? Cancer Genet. Cytogenet. 10: 139-142, 1983. [PubMed: 6577939] [Full Text: https://doi.org/10.1016/0165-4608(83)90117-6]
Vaesen, M., Barnikol-Watanabe, S., Gotz, H., Awni, L. A., Cole, T., Zimmermann, B, Kratzin, H. D., Hilschmann, N. Purification and characterization of two putative HLA class II associated proteins: PHAPI and PHAPII. Biol. Chem. Hoppe Seyler 375: 113-126, 1994. [PubMed: 8192856] [Full Text: https://doi.org/10.1515/bchm3.1994.375.2.113]
von Lindern, M., Fornerod, M., van Baal, S., Jaegle, M., de Wit, T., Buijs, A., Grosveld, G. The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA. Molec. Cell. Biol. 12: 1687-1697, 1992. [PubMed: 1549122] [Full Text: https://doi.org/10.1128/mcb.12.4.1687-1697.1992]
von Lindern, M., Poustka, A., Lehrach, H., Grosveld, G. The (6;9) chromosome translocation, associated with a specific subtype of acute nonlymphocytic leukemia, leads to aberrant transcription of a target gene on 9q34. Molec. Cell. Biol. 10: 4016-4026, 1990. [PubMed: 2370860] [Full Text: https://doi.org/10.1128/mcb.10.8.4016-4026.1990]
von Lindern, M., van Baal, S., Wiegant, J., Raap, A., Hagemeijer, A., Grosveld, G. Can, a putative oncogene associated with myeloid leukemogenesis may be activated by fusion of its 3-prime half to different genes: characterization of the set gene. Molec. Cell Biol. 12: 3346-3355, 1992. [PubMed: 1630450] [Full Text: https://doi.org/10.1128/mcb.12.8.3346-3355.1992]
Wang, Y., Zhang, H., Na, L., Du, C., Zhang, Z., Zheng, Y.-H., Wang, X. ANP32A and ANP32B are key factors in the Rev-dependent CRM1 pathway for nuclear export of HIV-1 unspliced mRNA. J. Biol. Chem. 294: 15346-15357, 2019. [PubMed: 31444273] [Full Text: https://doi.org/10.1074/jbc.RA119.008450]
Zhang, H., Zhang, Z., Wang, Y., Wang, M., Wang, X., Zhang, X., Ji, S., Du, C., Chen, H., Wang, X. Fundamental contribution and host range determination of ANP32A and ANP32B in influenza A virus polymerase activity. J. Virol. 93: e00174-19, 2019. [PubMed: 30996088] [Full Text: https://doi.org/10.1128/JVI.00174-19]