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2017 ; 2
(20
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Human alternative Klotho mRNA is a nonsense-mediated mRNA decay target
inefficiently spliced in renal disease
#MMPMID29046474
Mencke R
; Harms G
; Moser J
; van Meurs M
; Diepstra A
; Leuvenink HG
; Hillebrands JL
JCI Insight
2017[Oct]; 2
(20
): ä PMID29046474
show ga
Klotho is a renal protein involved in phosphate homeostasis, which is
downregulated in renal disease. It has long been considered an antiaging 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 IP 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 colocalized
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 2 mRNA transcripts is dysregulated, which
was recapitulated by various noxious stimuli in vitro. This likely constitutes a
novel mechanism resulting in the downregulation of membrane-bound Klotho.
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