The human “secreted Klotho” alternative mRNA is a nonsense-mediated mRNA decay target and its splicing is dysregulated in renal disease

Mencke, R., Harms, G., Moser, J., van Meurs, M., Diepstra, A., Leuvenink, H. G. D. & Hillebrands, J-L. 14-Sep-2017 (Accepted/In press) In : JCI Insight. 63 p.

Research output: Scientific - peer-reviewArticle

Klotho is a renal protein involved in phosphate homeostasis, which is down-regulated in renal
disease. It has long been considered an anti-ageing factor. Two Klotho gene transcripts are
thought to encode membrane-bound and secreted Klotho. Indeed, soluble Klotho is detectable in bodily fluids, but the relative contributions of Klotho secretion and of membrane-bound Klotho shedding are unknown. Recent advances in RNA surveillance reveal that premature termination codons, as present in alternative Klotho mRNA (for secreted Klotho), prime mRNAs for degradation by nonsense-mediated mRNA decay (NMD). Disruption of NMD led to accumulation of alternative Klotho mRNA, indicative of normally continuous degradation. RNA immunoprecipitation for NMD core factor UPF1 resulted in enrichment for alternative Klotho mRNA, which was also not associated with polysomes, indicating no active protein translation. Alternative Klotho mRNA transcripts co-localized with some P bodies, where NMD transcripts are degraded. Moreover, we could not detect secreted Klotho in vitro. These results suggest that soluble Klotho is likely cleaved membrane-bound Klotho only. Furthermore, we found that especially in acute kidney injury, splicing of the two mRNA transcripts is dysregulated, which was recapitulated by various noxious stimuli in vitro. This likely constitutes a novel mechanism resulting in the down-regulation of membrane-bound Klotho.
Original languageEnglish
Number of pages63
JournalJCI Insight
StateAccepted/In press - 14-Sep-2017

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