The recently discovered circular RNAs (circRNAs) are mostly formed by back-splicing where the down-stream 5' splice site splices to the upstream 3' splice site by conventional pre-mRNA splicing. These circRNAs regulate gene expression by acting as sponges for micro-RNAs or RNA-binding proteins. Here we show that the NR5A1 (previously called Ad4BP or SF-1) gene which is exclusively expressed in the adrenal cortex and steroidogenic tissue can form atypical circRNAs by unconventional splicing. Two stem loops with inositol-requiring protein-1 alpha (IRE1 alpha) cleavage sites are connected by an IRE1 alpha cleavage site to form a circRNA (circlRE RNA). From total RNA of normal human adrenal cortex, we detected a circlRE RNA with connected ends by IRE1 alpha cleavage sites in exon 6 and exon 1 (circlRE NR5A1 ex6-1 RNA). circlRE NR5A1 ex6-1 RNA was not detected in the adrenocortical cancer cell line, H295R. When IRE1 alpha was expressed in H295R cells a different circlRE NR5A1 RNA connecting IRE1-cleavage sites in exon 7 and exon 1 was detected (circlRE NR5A1 ex7-1 RNA). The expression of this circlRE RNA was inhibited by the IRE1 inhibitor 1, STF-083010, implicating that it was formed via the ER stress pathway, where IRE1 alpha is a major factor. This is the first report of this type of circular RNA connected by IRE1-cleavage sites found to be expressed in mammalian cells in a tissue-specific manner. To our surprise, the concomitant expression of NR5A1 was increased by IRE1 alpha implicating that NR5A1 was not subjected to IRE1-dependent decay of mRNA (RIDD) but rather activating a transcriptional regulatory network to cope with ER stress in steroidogenic tissue reminiscent to XBP1 in other tissue. We believe this is the first report of such tissue specific transcriptional cascade responding to ER stress as well as the novel finding of circular RNAs connected by IRE1 alpha cleavage sites expressed in mammalian tissue. (C) 2019 Elsevier Inc. All rights reserved.