Slo2 channels are large-conductance potassium channels existing in mammals as well as invertebrates (Kaczmarek, 2013; Yuan et al., 2000). They are the primary conductor of delayed outward currents in many neurons examined (Budelli et al., 2009; Liu et al., 2014). Human and mouse each has two Slo2 channels (Slo2.1/Slick and Slo2.2/Slack) (Kaczmarek, 2013), whereas the nematode C. elegans has only one (SLO-2). These channels are abundantly expressed in the nervous system (Bhattacharjee et al., 2002; Bhattacharjee et al., 2005; Joiner et al., 1998; Liu et al., 2018; Rizzi et al., 2016), and play major roles in shaping neuronal electrical properties and regulating neurotransmitter release (Kaczmarek, 2013; Liu et al., 2014). Mutations of Slo2 channels cause epilepsies and severe intellectual disabilities in humans (Ambrosino et al., 2018; Cataldi et al., 2019; Evely et al., 2017; Gururaj et al., 2017; Hansen et al., 2017; Kawasaki et al., 2017; Lim et al., 2016; McTague et al., 2018; Rizzo et al., 2016), and reduced tolerance to hypoxic environment in worms (Yuan et al., 2003). Emerging evidence suggests that physiological functions of these channels depend on other proteins. For example, in mice, the fragile mental retardation protein (FMRP), a RNA binding protein, enhances Slack activity by binding to its carboxyl terminus (Brown et al., 2010). In worms, HRPU-2, a RNA/DNA binding protein, controls the expression level of SLO-2 through a posttranscriptional effect (Liu et al., 2018).

RNA editing is an evolutionally conserved post-transcriptional process catalyzed by ADARs (adenosine deaminases acting on RNA) (Gott and Emeson, 2000; Jin et al., 2009). ADARs convert adenosine (A) to inosine (I) in double-stranded RNA. Since inosine is interpreted as guanosine (G) by cellular machineries (Basilio et al., 1962), A-to-I RNA editing may alter the function of a protein by changing its coding potential, or regulate gene expression through altering alternative splicing, microRNA processing, or RNA interference (Deffit and Hundley, 2016; Nishikura, 2016). Human and mouse each has three ADARs: ADAR1, ADAR2 and ADAR3 (Chen et al., 2000; Kim et al., 1994; Melcher et al., 1996). ADAR1 and ADAR2 possess deaminase activity and catalyze the A-to-I conversion (Tan et al., 2017), whereas ADAR3 is catalytically inactive with regulatory roles in RNA editing (Nishikura, 2016). Millions of A-to-I editing sites have been detected in the human transcriptome through RNA-seq, with the vast majority of them found in non-coding regions (Nishikura, 2016). Biological effects of RNA editing at coding regions have been revealed for a variety of genes, including those encoding ligand- and voltage-gated ion channels and G protein-coupled receptors (Bhalla et al., 2004; Brusa et al., 1995; Burns et al., 1997; Gonzalez et al., 2011; Huang et al., 2012; Lomeli et al., 1994; Palladino et al., 2000; Rula et al., 2008; Sommer et al., 1991; Streit et al., 2011). However, little is known about the roles of RNA editing in non-coding regions (Nishikura, 2016).

In a genetic screen for suppressors of a sluggish phenotype caused by expressing a hyperactive SLO-2 in worms, we isolated mutants of several genes, including adr-1, which encodes one of two ADARs in C. elegans (ADR-1 and ADR-2). While ADR-2 has deaminase activity and plays an indispensable role in the A-to-I conversion, ADR-1 is catalytically inactive but can promote RNA editing by binding to selected target mRNA and tethering ADR-2 to RNA substrates (Ganem et al., 2019; Rajendren et al., 2018; Washburn et al., 2014). We found that loss-of-function (lf) mutations of adr-1 inhibit SLO-2 function through impairing RNA editing of scyl-1, which encodes an orthologue of human and mouse SCYL1. In adr-1(lf) mutants, a lack of A-to-I conversion at a specific site in scyl-1 3’-UTR causes reduced scyl-1 expression. Knockout of scyl-1 severely reduces SLO-2 current in worms whereas coexpression of SCYL1 with human Slack in Xenopus oocytes greatly augments channel activity. These results suggest that SCYL-1/SCYL1 proteins likely play an evolutionarily conserved role in physiological functions of Slo2 channels. Mutations or knockout mammalian SCYL1 may cause neural degeneration, intellectual disabilities, and liver failure, but the underlying mechanisms are unclear (Lenz et al., 2018; Li et al., 2019; Shohet et al., 2019; Spagnoli et al., 2019). The revelation of SCYL-1/SCYL1 as a protein important to Slo2 channels suggests a potential link between diseases caused by SCLY1 mutations and Slo2 channel functions.

This study shows that both ADR-1 and SCYL-1 are critical to SLO-2 physiological function in neurons. While ADR-1 enhances SLO-2 function indirectly through promoting SCYL-1 expression, SCYL-1 regulates SLO-2 through physical interactions. These conclusions are supported by multiple lines of evidence, including the isolation of adr-1(lf) mutants as suppressors of SLO-2(gf), the inhibition of SLO-2 activities by either adr-1(lf) or scyl-1(lf), the reduction of scyl-1 transcript expression in adr-1(lf), the correlation between scyl-1 mRNA level and RNA editing at its 3’-UTR, the evidence of physical interactions between SCYL-1 and SLO-2, and the reduction of SLO-2 P_o due to changes in the dwell times of open and closed events in scyl-1(lf). Importantly, we found that the human Slo2.2/Slack is also regulated by SCYL1.

The biological significance of RNA editing at non-coding regions is only beginning to be appreciated. A recent study with C. elegans identified many neuron-specific A-to-I editing sites in the 3’-UTR of clec-41, and showed that elimination of these editing events by adr-2 knockout compromises clec-41 expression and impairs a chemotaxis behavior (Deffit et al., 2017). However, it remains to be determined how clec-41 expression is controlled by these editing events, and whether the chemotaxis defect of adr-2(lf) mutant is caused by decreased clec-41 expression. In the present study, we demonstrate that an A-to-I RNA editing event at the 3’UTR of scyl-1 controls its expression, and that SCYL-1 contributes to neuronal whole-cell currents through a direct effect on SLO-2. The results of these two studies have provided a glimpse of the biological roles of 3’-UTR RNA editing in gene expression and neuronal function.

Our results demonstrate that RNA editing at a single site in the 3’-UTR could have a profound effect on gene expression. The A-to-I conversion at the ADR-1-regulated editing site increases base pairing in the putative double-stranded structure of scyl-1 3’-UTR (Figure 10B). Increased base paring in a double-stranded RNA generally facilitates RNA degradation. It is therefore intriguing how such an editing event may cause increased gene expression. One possibility is that editing at this site helps maintain mRNA stability through recruiting other regulatory proteins to the 3’-UTR. The isolation of mutants exhibiting diminished GFP expression from a reporter construct containing the edited scyl-1 3’-UTR but not the unc-10 3’-UTR (Figure 10—figure supplement 1) indicates potential existence of such regulatory proteins. In combination with the observation that GFP signal was undetectable in transgenic worms expressing a reporter construct containing the non-edited scyl-1 3’-UTR, this result suggests that RNA editing at the ADR-1-dependent site in scyl-1 3’-UTR is likely important to recruiting the putative regulatory proteins to increase mRNA stability.

scyl-1 has four different transcripts with identical 5’-UTR and coding sequence but different 3’-UTRs of variable lengths (ranging from 167 to 1862 nucleotides) and sequences (www.wormbase.org). The ADR-1-dependent editing site exists only in the transcript with the longest 3’-UTR. The presence of an ADR-1-regulated editing site in this but not the other transcripts suggests that ADR-1 may regulate scyl-1 expression in a cell-specific manner depending on where the specific transcript is expressed. Interestingly, the 3’-UTR of human SCYL1 transcripts (NM_020680.4) also has a high probability of forming hair-pin structures based on software prediction (https://rna.urmc.rochester.edu/RNAstructureWeb/Servers). It remains to be determined whether human SCYL1 transcripts are also edited in the 3’-UTR, and if so, whether the editing regulates their expression.

SCYL1 proteins are evolutionarily conserved proteins that share an N-terminal pseudokinase domain (Manning et al., 2002; Pelletier, 2016). Results of previous studies with cultured cells suggest that SCYL1 may regulate intracellular trafficking between the Golgi apparatus and the ER (Burman et al., 2008; Burman et al., 2010), and facilitate nuclear tRNA export by acting at the nuclear pore complex (Chafe and Mangroo, 2010). Mutations of SCYL1 in humans are associated with a variety of disorders, including neurodegeneration, intellectual disabilities, and liver failure (Lenz et al., 2018; Li et al., 2019; Schmidt et al., 2015; Shohet et al., 2019; Spagnoli et al., 2019). Mice with SCYL1 deficiency develop an early onset and progressive neurodegenerative disorder (Pelletier et al., 2012). However, it is unclear whether the documented mutant phenotypes of SCYL1 are related to its roles in intracellular trafficking and nuclear tRNA export (Pelletier, 2016). This study brings into view a new potential mechanism for SCYL1 mutation-associated disorders: impairing Slo2 channel function. What might be the molecular mechanism through which SCYL-1 enhances SLO-2 activity? Since SCYL-1 physically associates with SLO-2, and enhances SLO-2 single-channel P_o by altering the open and closed states, it likely regulates channel function either directly or through a closely associated protein. Although the exact mechanism remains to be determined, the similar effects of SCYL-1 and SCYL1 on Slo2 channels suggest that they likely play an important role in Slo2 physiological functions across animal species.

The expression patterns of scyl-1 and slo-2 largely do not overlap. Although they are coexpressed in ventral cord motor neurons, most other neurons expressing slo-2 do not express scyl-1, suggesting that the regulatory effect of SCYL-1 on SLO-2 is cell- and tissue-specific. The expression of scyl-1 in cells not expressing slo-2 suggests that SCYL-1 physiological functions are not limited to regulating SLO-2. In mouse, SCYL1 and Slo2.2 are both expressed in the hippocampus and cerebellum but their expression patterns do not completely overlap (Joiner et al., 1998; Schmidt et al., 2007). Conceivably, the regulation of hSlo2.2 by SCYL1 might also occur in a cell- and tissue-specific manner, and SCYL1 likely performs other physiological functions. The latter possibility is supported by the pleiotropic phenotypes observed in patients and mice with SCYL1 mutations (Lenz et al., 2018; Li et al., 2019; Pelletier et al., 2012; Schmidt et al., 2015; Shohet et al., 2019; Spagnoli et al., 2019).

In summary, this study demonstrates that ADAR-mediated RNA editing controls the expression of SCYL-1, which interacts with SLO-2 to allow SLO-2 perform its physiological functions. Moreover, this study shows that this regulatory mechanism is conserved with mammalian SCYL1 and Slo2. Our findings reveal a new molecular mechanism of Slo2 channel regulation, and provide the bases for investigating how physiological functions of human Slo2 are regulated by SCYL1, and whether the neurodegeneration and intellectual disability phenotypes of SCYL1 mutations are related to Slo2 channel dysfunction.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 4, 5, 7, 8, 10,and 11. Sequencing data have been deposited in GEO under accession code GSE141316.

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Author details

1. Long-Gang Niu

   Department of Neuroscience, University of Connecticut Health Center, Farmington, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

2. Ping Liu

   Department of Neuroscience, University of Connecticut Health Center, Farmington, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Zhao-Wen Wang

   Department of Neuroscience, University of Connecticut Health Center, Farmington, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing - review and editing

   Competing interests

   No competing interests declared

4. Bojun Chen

   Department of Neuroscience, University of Connecticut Health Center, Farmington, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   bochen@uchc.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1141-9101

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