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Deficiency of Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Leads to Progressive Loss of Photoreceptor Function

Författare och institution:
J. R. Christiansen (-); N. D. Pendse (-); S. Kolandaivelu (-); Martin Bergö (Sahlgrenska Cancer Center); S. G. Young (-); V. Ramamurthy (-)
Publicerad i:
Journal of Neuroscience, 36 ( 18 ) s. 5107-5114
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
Retinal neurons use multiple strategies to fine-tune visual signal transduction, including post-translational modifications of proteins, such as addition of an isoprenyl lipid to a carboxyl-terminal cysteine in proteins that terminate with a "CAAX motif." We previously showed that RAS converting enzyme 1 (RCE1)-mediated processing of isoprenylated proteins is required for photoreceptor maintenance and function. However, it is not yet known whether the requirement for the RCE1-mediated protein processing is related to the absence of the endoproteolytic processing step, the absence of the subsequent methylation step by isoprenylcysteine methyltransferase (ICMT), or both. To approach this issue and to understand the significance of protein methylation, we generated mice lacking Icmt expression in the retina. In the absence of Icmt expression, rod and cone light-mediated responses diminished progressively. Lack of ICMT-mediated methylation led to defective association of isoprenylated transducin and cone phosphodiesterase 6 (PDE6 alpha') with photoreceptor membranes and resulted in decreased levels of transducin, PDE6 alpha', and cone G-protein coupled receptor kinase-1 (GRK1). In contrast to our earlier findings with retina-specific Rce1 knock-out mice, rod PDE6 in Icmt-deficient mice trafficked normally to the photoreceptor outer segment, suggesting that the failure to remove the - AAX is responsible for blocking the movement of PDE6 to the outer segment. Our findings demonstrate that carboxyl methylation of isoprenylated proteins is crucial for maintenance of photoreceptor function.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Klinisk medicin ->
electroretinogram, phototransduction cascade, post-translational protein modification, protein methylation, protein stability, retinal neurons, phosphodiesterase catalytic subunits, rod outer segments, gamma-subunit, membrane association, mouse model, k-ras, methylation, binding, proteins, cells, Neurosciences & Neurology
Postens nummer:
Posten skapad:
2016-07-27 15:12

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