Abstract 11247: The Long Noncoding MALAT1 - MascRNA System is a Novel Regulator of Cardiac Innate Immunity
Background: Regarding disease pathogenesis, it has become evident that confinement to analysis of protein-coding regions of the genome is insufficient since many noncoding regions are associated with human diseases. We searched for elements of the noncoding genome influencing the highly variable course of a cardiomyopathy caused by a common single-stranded RNA virus (CVB3).
Methods and Results: Transcriptome mapping of human CVB3 cardiomyopathy hearts showed high long noncoding RNAs (lncRNA) MALAT1 associated with spontaneous virus clearance and recovery, and low MALAT1 with virus persistence and clinical deterioration. Primary [[Unable to Display Character: ]]7kb MALAT1 transcript is only part of a complex RNA processing system generating e.g. mascRNA, a tRNA-like molecule, by a novel biosynthetic pathway. First, we found cell type-specific MALAT1 processing to result in grossly different mascRNA levels, which were highest in leukocytes. Second, CVB3 infection of genetically MALAT1-deficient (MALAT1-/-) mice resulted in anomalous splenic immune cell subtype distribution and function, and altered splenic and cardiac transcriptomes involving chemokine/receptor systems and antiviral genes. Third, recombinant mascRNA overexpression in primary cardiomyocytes induced IFIT genes coding an antiviral protein complex addressing 5’-triphosphate and 2’-O methylated RNA, and IFITM genes inhibiting multiple RNA viruses. Functionally, recombinant mascRNA blocked CVB3 replication in cardiomyocytes, inducing IFITs and IFITMs and immunoproteasome subunits, whereas the common time-delayed induction of interferons after infection was lacking.
Conclusions: These data indicate that the MALAT1-mascRNA system is a novel regulator of cardiac innate immunity influencing heart-immune system interactions e.g. during viral infections. mascRNA mimics or pharmacological modulation of the MALAT1-mascRNA system may have therapeutic potential.
Author Disclosures: W. Poller: None. M. Gast: None. B. Schroen: None. A. Voigt: None. J. Haas: None. A. Papageorgiou: None. U. Kuehl: None. D. Lassner: None. X. Wang: None. M. Loebel: None. S. Wilk: None. N. Althof: None. T. Peters: None. K. Prasanth: None. H. Katus: None. B. Meder: None. S. Nakagawa: None. C. Scheibenbogen: None. S. Heymans: None.
- © 2014 by American Heart Association, Inc.