title: The tumor suppressor annexin A10 is a novel component of nuclear paraspeckles.
abstract: Annexin A10 is the latest identified member of the annexin family of Ca(2+)- and phospholipid-binding proteins. In previous studies, downregulation of annexin A10 was correlated with dedifferentiation, invasion, and tumor progression, pointing to a possible tumor suppressor role. However, the biochemical characteristics and functions of annexin A10 remain unknown. We show that annexin A10 displays biochemical characteristics atypical for an annexin, indicating a Ca(2+)- and membrane-binding-independent function. Annexin A10 co-localizes with the mRNA-binding proteins SFPQ and PSPC1 at paraspeckles, an only recently discovered nuclear body, and decreases paraspeckle numbers when overexpressed in HeLa cells. In addition, annexin A10 relocates to dark perinucleolar caps upon transcriptional inhibition of RNA polymerase II. We mapped the cap-binding function of annexin A10 to the proximal part of the core domain, which is missing in the short isoform of annexin A10, and show its independence from the remaining functional type II Ca(2+)-binding site. In contrast to this, paraspeckle recruitment required additional core regions and was negatively affected by the mutation of the last type II Ca(2+)-binding site. Additionally, we show that overexpression of annexin A10 in HeLa cells increases their sensitivity to apoptosis and reduces colony formation. The identification of unique nuclear and biochemical characteristics of annexin A10 points towards its membrane-independent role in paraspeckle-associated mRNA regulation or processing.
authors.affiliation: Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, and Interdisciplinary Clinical Research Centre, University of Münster, 48149, Münster, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Quiskamp
authors.forename: Michaela
authors.initials: M
authors.lastname: Poeter
authors.forename: Carsten Alexander
authors.initials: CA
authors.lastname: Raabe
authors.forename: Ulli Martin
authors.initials: UM
authors.lastname: Hohenester
authors.forename: Simone
authors.initials: S
authors.lastname: König
authors.forename: Volker
authors.initials: V
authors.lastname: Gerke
authors.forename: Ursula
authors.initials: U
authors.lastname: Rescher
mesh_terms: D000818:Animals; D017302:Annexins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D004285:Dogs; D004317:Doxorubicin / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D009687:Nuclear Proteins / Q000378:metabolism; D000072670:PTB-Associated Splicing Factor; D020033:Protein Isoforms / Q000378:metabolism; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: C121387:ANXA10 protein, human; D017302:Annexins; D000903:Antibiotics, Antineoplastic; D009687:Nuclear Proteins; C450059:PSPC1 protein, human; D000072670:PTB-Associated Splicing Factor; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D004317:Doxorubicin; D012319:RNA Polymerase II; D002118:Calcium