Klotho (biology)

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Klotho
Identifiers
Symbol KL
External IDs OMIM604824 MGI1101771 HomoloGene68415 GeneCards: KL Gene
EC number 3.2.1.31
Orthologs
Species Human Mouse
Entrez 9365 16591
Ensembl ENSG00000133116 ENSMUSG00000058488
UniProt Q9UEF7 O35082
RefSeq (mRNA) NM_004795 NM_013823
RefSeq (protein) NP_004786 NP_038851
Location (UCSC) Chr 13:
33.59 – 33.64 Mb
Chr 5:
150.95 – 150.99 Mb
PubMed search [1] [2]

Klotho is an enzyme that in humans is encoded by the KL gene.[1]

This gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss.[2] Transgenic mice that overexpress Klotho live longer than wild-type mice.[3]

Function[edit]

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in aging. Its discovery was documented in 1997 by Kuro-o et al.[4] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[5] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[6]

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[7] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations. [8]

The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.[9] Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.[9] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).[10][11][12][13]

References[edit]

  1. ^ Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (January 1998). "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochem. Biophys. Res. Commun. 242 (3): 626–30. doi:10.1006/bbrc.1997.8019. PMID 9464267. 
  2. ^ "Entrez Gene: klotho". 
  3. ^ Kurosu, H.; Yamamoto, M.; Clark, J. D.; Pastor, J. V.; Nandi, A.; Gurnani, P.; McGuinness, O. P.; Chikuda, H.; Yamaguchi, M.; Kawaguchi, H.; Shimomura, I.; Takayama, Y.; Herz, J.; Kahn, C. R.; Rosenblatt, K. P.; Kuro-o, M. (2005). "Suppression of Aging in Mice by the Hormone Klotho". Science 309 (5742): 1829–1833. Bibcode:2005Sci...309.1829K. doi:10.1126/science.1112766. PMC 2536606. PMID 16123266.  edit
  4. ^ Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (November 1997). "Mutation of the mouse klotho gene leads to a syndrome resembling ageing". Nature 390 (6655): 45–51. Bibcode:1997Natur.390...45K. doi:10.1038/36285. PMID 9363890. 
  5. ^ Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (January 2002). "Association of human aging with a functional variant of klotho". Proc. Natl. Acad. Sci. U.S.A. 99 (2): 856–61. Bibcode:2002PNAS...99..856A. doi:10.1073/pnas.022484299. PMC 117395. PMID 11792841. 
  6. ^ Xiao NM, Zhang YM, Zheng Q, Gu J (May 2004). "Klotho is a serum factor related to human aging". Chin. Med. J. 117 (5): 742–7. PMID 15161545. 
  7. ^ Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (September 2005). "Suppression of aging in mice by the hormone Klotho". Science 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. doi:10.1126/science.1112766. PMC 2536606. PMID 16123266. 
  8. ^ Dena B. Dubal et al., Life Extension Factor Klotho Enhances Cognition, Cell Reports, 2014, DOI: 10.1016/j.celrep.2014.03.076 (open access)
  9. ^ a b Huang, C. L. (2010). "Regulation of ion channels by secreted Klotho: Mechanisms and implications". Kidney International 77 (10): 855–860. doi:10.1038/ki.2010.73. PMID 20375979.  edit
  10. ^ Kuro-O, M. (2009). "Klotho and aging". Biochimica et Biophysica Acta 1790 (10): 1049–1058. doi:10.1016/j.bbagen.2009.02.005. PMC 2743784. PMID 19230844.  edit
  11. ^ Medici, D.; Razzaque, M. S.; Deluca, S.; Rector, T. L.; Hou, B.; Kang, K.; Goetz, R.; Mohammadi, M.; Kuro-o, M.; Olsen, B. R.; Lanske, B. (2008). "FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis". The Journal of Cell Biology 182 (3): 459–465. doi:10.1083/jcb.200803024. PMC 2500132. PMID 18678710.  edit
  12. ^ Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (December 2003). "Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system". Mol. Endocrinol. 17 (12): 2393–403. doi:10.1210/me.2003-0048. PMID 14528024. 
  13. ^ Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y (June 2007). "alpha-Klotho as a regulator of calcium homeostasis". Science 316 (5831): 1615–8. Bibcode:2007Sci...316.1615I. doi:10.1126/science.1135901. PMID 17569864. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.