Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Chad N. Brocker; Donghwan Kim; Tisha Melia; Kritika Karri; Thomas J. Velenosi; Shogo Takahashi; Jessica A. Bonzo; David J. Waxman; Frank J. Gonzalez

An internal ribosome entry site (IRES) is an RNA element that allows for translation initiation (Lampe et al., 2018) . Deregulation of IRES-mediated p53 translation promoted the defective p53 response against DNA damage in human cancer cells (Halaby et al., 2015) . ER stress, serum deprivation, and hypoxia-induced human acetyl-CoA carboxylase 1 (hACC1) are controlled by IRES sequences (Damiano et al., 2018) . Beclin-1 independent autophagy is promoted through IRES-dependent translation of hypoxia-inducible factor 1α (HIF1α) (Wu et al., 2014) . Polypyrimidine tract binding proteins (PTBs) were shown to regulate TXNIP expression . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/675785 doi: bioRxiv preprint during nutrition starvation by binding to IRES sequences within the Txnip 5'UTR (Lampe et al., 2018) . By binding to these IRES sequences, PTB prevents translation initiation and suppresses TXNIP protein expression. As lncRNA Gm15441 is antisense to TXNIP and its exon 3 almost entirely overlaps the Txnip 5'UTR, Gm15441 may block IRES sequences needed for translation of TXNIP. The ability of Gm15441 to modulate TXNIP protein levels via Txnip 5'UTR IRES sequences was demonstrated in vitro by co-transfection of a GFP reporter with a Gm15441 expression vector. A decrease in GFP expression was dependent on both Gm15441 mRNA and the Txnip 5'UTR sequence, indicating that Gm15441 in part regulates TXNIP by binding to its 5'UTR, presumably by masking functional IRES sites.