Department of Surgery, State University of New York Downstate Health Sciences University, Brooklyn, New York, USA
Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
Department of Management Science and Engineering, Stanford University, Stanford, California, USA
Burlingame High School, Burlingame, CA, USA
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York, USA
† These authors contributed equally to this work.
Academic Editor: Michael R. Ladomery
Received: March 23, 2020 | Accepted: May 15, 2020 | Published: May 22, 2020
OBM Genetics 2020, Volume 4, Issue 2, doi:10.21926/obm.genet.2002110
Recommended citation: Song Y, Rivera C, Mai J, Sun A, Li W. Splicing HAC1/XBP1 mRNAs in Cytoplasm: The Non-Conventional mRNA Splicing Reaction in the Unfolded Protein Response. OBM Genetics 2020;4(2):11; doi:10.21926/obm.genet.2002110.
© 2020 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
In eukaryotes, both transfer RNAs (tRNAs) and messenger RNAs (mRNAs) are subject to splicing. But the tRNA and mRNA splicing are biochemically distinct processes that utilize different molecular machineries. Precursor tRNAs are cleaved at two splice sites by the tRNA endoribonuclease, which are located mostly in nucleus for metazoans and in cytosol for Saccharomyces cerevisiae . As a consequence, the precursor tRNAs are spitted into three pieces—the 5’-half tRNA, the intron and the 3’-half tRNA. Then, tRNA ligase joins the 5’- and 3’-half tRNA, forming the spliced tRNA [2,3]. In comparison, the mRNA splicing is catalyzed in the nucleus by the spliceosome, which is composed of small nuclear RNAs and about 80 proteins . Unlike the tRNA splicing reaction, the mRNA splicing reaction produces a lariat intermediate instead of cleavage fragments [4,5,6]. While tRNA and mRNA splicing are two independent processes, one mRNA—HAC1 mRNA in S. cerevisiae and XBP1 mRNA in metazoan—undergoes a non-conventional mRNA splicing reaction, which biochemically resembles the tRNA splicing reaction. The non-conventional mRNA splicing reaction was independently discovered by Peter Walter’s and Kazutoshi Mori’s lab in the 1990s when they discovered the unfolded protein response (UPR), which is a signaling pathway that maintains the protein folding homeostasis in the endoplasmic reticulum (ER) (Figure 1A) [7,8,9,10,11,12]. Under normal condition, the HAC1 mRNA contains a 252-nt intron. The intron forms a long-range basepairing with the HAC1 mRNA 5’ UTR and creates a translational block. As a result, the un-spliced HAC1 mRNA is not translated [13,14,15]. When unfolded proteins accumulate in the ER, a condition termed ER stress, the HAC1 mRNA is cleaved by an endoribonuclease, Ire1, resulting in three intermediate fragments—the 5’ exon, the intron and the 3’ exon . Then, the two exons undergo a conformational change, which positions the ends of the exons in close proximity [17,18]. Then, the tRNA ligase joins the 5’ and 3’ exons and completes the splicing reaction . The spliced HAC1 mRNA produces the transcription factor Hac1, which transcriptionally increases the ER chaperone and the ER volume [7,8,20]. The ER-associated degradation is upregulated to degrade the unfolded proteins [21,22,23]. As a result, the ER’s protein folding capacity increases and the proteins folding homeostasis is restored. The non-conventional mRNA splicing reaction is an evolutionarily conserved process of the UPR . Mis-regulation of UPR leads to pathological effects. For example, prolonged UPR activation in pancreatic b-cells, in which large amount of insulin is produced, leads to apoptosis and type II diabetes . Another example is that enveloped virus infections hijack the UPR pathways to increase ER folding capacity and assist in viral replication [26,27]. Readers may refer to these articles [28,29,30,31,32,33,34] for a more comprehensive review on the physiological role of the UPR in health and disease. In this article, we summarize recent studies that focus on understanding the molecular mechanism of the HAC1/XBP1 mRNA splicing reaction.
2. The Cleavage of the HAC1/XBP1 mRNA is Mediated by the Kinase/Endoribonuclease Ire1
Ire1 is a single-pass transmembrane protein on the ER. Ire1 has an ER lumenal domain and a cytosolic kinase/endoribonuclease (RNase) domain. S. cerevisiae has one Ire1 homolog while mammalian cells have two Ire1 paralogs: Ire1a, expressed ubiquitously throughout the body, and Ire1b, expressed only in the epithelial cells of airways and intestines [35,36,37,38]. Both mammalian Ire1a and Ire1b catalyze the XBP1 mRNA splicing, but with different efficiency [9,39,40]. Upon ER stress, Ire1’s lumenal domain senses the unfolded proteins and triggers Ire1 to oligomerize [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56]. The oligomerized Ire1 undergoes trans-autophosphorylation, which activates the RNase domain [53,57,58,59,60]. A recent study discovered that the RNase activation is mediated by an interdomain helix between the Ire1’s kinase and RNase domains . The activated RNase domain cleaves the HAC1/XBP1 mRNA at the two splice sites, separating the two exon fragments from the intron fragment [16,62]. The Ire1-mediated cleavage is the first step of the non-conventional mRNA splicing.
The substrate specificity of Ire1’s RNase domain ensures that the cleavages only occur at the two splice sites on the HAC1/XBP1 mRNAs. S. cerevisiae Ire1 recognizes CNG|CNGN or CNG|ANGN (“|” represents the cleavage site) on a stem loop, of which the loop size is 7 [18,62,63]. Mammalian Ire1a recognizes CNG|CNGN on a stem loop, of which the loop size ranges from 5 to 9 [18,64,65,66]. Recent findings showed that the Ire1’s RNase specificity is regulated by its phosphorylation and oligomeric state [57,67,68,69]. In a study by Tam and colleagues , they found that the yeast Ire1 has a stringent RNase activity when forming high-order oligomers but has a promiscuous RNase activity when forming low-order oligomers (like dimers). In contrast, in a study by Han and colleagues , they found that the mammalian Ire1a has a promiscuous RNase activity when forming high-order oligomers but has a stringent RNase activity when forming low-order oligomers. Further studies are needed to reconcile the two observations and gain a structural understanding on the Ire1’s RNase specificity.
3. An RNA Conformational Change Prepares the HAC1/XBP1 mRNA Exons for Ligation
Post Ire1-mediated cleavages, three intermediate fragments are produced: the 5’ exon, the intron and the 3’ exon. A recent study reported that an RNA conformational change positions the ends of the exons in close proximity to prepare them for the subsequent ligation reaction . Specifically, the flanking sequence of the two splice sites on HAC1/XBP1 mRNA is predicted to form a secondary structure, which resembles the letter “Y” (Figure 1A). The Y-shaped RNA structure has three stems: the central stem (S1) and the two arm stems (S2 and S3). The two spliced sites are located on the stem-loops of S2 and S3. Post Ire1-mediated cleavages, the S2 and S3 stems are replaced by an extended S1 stem. As a result, this conformational change ejects the intron and physically tethers the two exons together. The ends of the two exons are positioned in close proximity, ready for the ligation reaction. If the Y-shaped structure is disrupted, the mutant mRNA cannot be efficiently ligated .
The importance of the Y-shaped RNA structure is further highlighted in our recent study, in which we reconstituted the non-conventional mRNA splicing reaction in vivo . Our study was performed in Schizosaccharomyces pombe, where the HAC1/XBP1 homolog is absent [70,71]. Instead of catalyzing the non-conventional mRNA splicing, the S. pombe Ire1 selectively cleaves and degrades a set of mRNAs at the ER periphery. This process, known as the regulated Ire1-dependent mRNA decay (RIDD), reduces influx of ER protein folding burden and restores ER homeostasis . RIDD was first discovered in Drosophila melanogaster and later found to be evolutionarily conserved [39,66,72,73,74,75,76,77,78,79]. RIDD is important for tissues undergoing intense secretory function, like the pancreatic b-cells [68,80]. RIDD mRNA substrates contain the consensus sequence and structure motif that can be recognized by Ire1 [18,65,66]. These mRNAs are cleaved in the vicinity of ER translocons, where the mRNAs are translated [72,81,82]. Unlike HAC1/XBP1 mRNAs, RIDD mRNAs lack the Y-shaped structure to coordinate cleavage fragments. As a consequence, the fragments are physically separated post cleavage and degraded by housekeeping machineries, rather than being ligated by tRNA ligase (Figure 1B). To show the essential role of the Y-shaped RNA structure, we modified an S. pombe mRNA by replacing the Ire1 cleavage site with a Y-shaped RNA cassette, the modified mRNA was non-conventionally spliced by Ire1 in an ER-stress dependent manner. Thus, the Y-shaped RNA structure is the key element that separates a splicing substrate from a RIDD substrate (Figure 1A, B) [18,83]. Together, these results showed that the RNA conformational change is a critical step of the splicing reaction.
4. The Ligation of the HAC1/XBP1 mRNA Exons is Mediated by the tRNA Ligase
Sidrauski and colleagues first discovered that the yeast tRNA ligase Trl1 joins the two HAC1 mRNA exons. They found that a Trl1 mutant, which harbors a point mutation H148Y, cannot mediate the HAC1 mRNA splicing but can still mediate the tRNA splicing . The mechanism of this functional separation was recently uncovered based on the crystal structure of Trl1 . Trl1 H148Y was found to be located near the catalytic site and compromises the ligation kinetics of Trl1. As a result, the HAC1 mRNA 5’ and 3’ exons cannot be efficiently ligated and are degraded by the Ski exosome complex and Xrn1. Thus, the HAC1 mRNA splicing is a well-balanced kinetic competition between mRNA decay and ligation [84,85].
In metazoans, the identity of the ligase had been elusive because Trl1 is not evolutionarily conserved . In 2014, four labs independently reported that RTCB, which is the catalytic subunit of the metazoan tRNA ligase complex, and its co-factor archease ligate the XBP1 mRNA exons [87,88,89,90]. When RTCB or archease is conditionally knocked out, the XBP1 mRNA 5’ and 3’ exons cannot be ligated [87,88,89,90]. In professional secretory cells, like the plasma cells, depleting RTCB decreases its ER protein folding capacity and, subsequently, its antibody production . When simultaneously expressed in S. cerevisiae cells, mammalian RTCB and archease can catalyze the ligation reaction of yeast HAC1 mRNA exons . Interestingly, a recent study showed that a tyrosine phosphorylation on RTCB reduces the enzyme’s efficiency to ligate XBP1 mRNA exons, suggesting additional layers of regulation . Together, these studies showed that the tRNA ligase catalyzes the ligation step of the non-conventional mRNA splicing reaction in both fungi and metazoans.
5. Concluding Remarks
The non-conventional mRNA splicing reaction is a uniquely evolved process in the UPR. Much mechanistic insight has been gained in the past two decades. The process employs three essential elements, including two trans-acting proteins—Ire1 and tRNA ligase—and one cis-acting element—the Y-shaped RNA structure (Figure 1A). In contrast, RIDD substrates lack the Y-shaped RNA structure and are degraded post Ire1 cleavage (Figure 1B) . Even though both XBP1 mRNA splicing and RIDD alleviate ER stress, they have different physiological functions in mammalian cells. It was suggested that XBP1 mRNA splicing is cyto-protective while RIDD is involved in apoptosis [68,93,94,95,96]. A key question is to understand how the XBP1 mRNA splicing and RIDD are distinctively regulated. The heart of this question lies at the RNase specificity of Ire1. If Ire1’s RNase activity becomes promiscuous, the substrate scope of RIDD increases and RIDD dominates. On the other hand, if Ire1’s RNase activity becomes stringent, the substrate scope of RIDD decreases and XBP1 pathway dominates. Thus, future studies are needed to gain a structural understanding of Ire1’s RNase specificity.
Figure 1 The model of the non-conventional mRNA splicing and RIDD. (A) The model of the HAC1/XBP1 mRNA splicing. The red RNA segment represents the intron. Blue dashed lines mark the two Ire1 cleavage sites. Dashed arrow lines indicate the movements of the corresponding intron or exon. The RNA stems S1, S2 and S3 constitute the Y-shaped mRNA structure. (B) The model of the RIDD process. Blue dashed lines mark the Ire1 cleavage sites.
Manuscript drafting and editing: Y.S., C.R., J.M., A.S. and W.L.
This work is supported by High School Intern Program at University of California San Francisco (J.M.) and Howard Hughes Medical institute’s Exceptional Research Opportunities Program (C.R.).
The authors have declared that no competing interests exist.
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