Editors' ChoiceCell Biology

Sphingolipids and Retinal Degeneration

Science Signaling  01 Mar 2011:
Vol. 4, Issue 162, pp. ec62
DOI: 10.1126/scisignal.4162ec62

The sphingosine kinases, of which there are two in Drosophila melanogaster (Sk1 and Sk2), mediate the phosphorylation of sphingosine to yield sphingosine 1-phosphate (S1P) and of dihydrosphingosine (DHS) to yield DHS 1-phosphate (DHS1P). S1P is both an intracellular and extracellular signaling molecule in mammals, but less is known about the functions of DHS1P. Drosophila lacks the receptor for extracellular S1P; thus, Yonamine et al. performed gain- and loss-of-function studies of Sk1 and Sk2 in Drosophila to investigate the intracellular functions of S1P and DHS1P. Overexpression of Sk2, but not Sk1, in the Drosophila eye during development or induced expression after eye development led to degeneration of the photoreceptors and reduced abundance of Rhodopsin 1 (Rh1), the G protein–coupled receptor that senses light, and transient receptor potential (TRP), a calcium-conducting channel that is downstream of Rh1. A kinase-inactive form of Sk2 failed to induce degeneration or reduce the abundance of Rh1 or TRP. In a Drosophila cell line, Sk2 was localized both to the cytoplasm and to lysosomal membranes, whereas Sk1 was detected at the plasma membrane and in the cytoplasm. When Sk2 was overexpressed in the car mutant background, which is deficient in delivery of plasma membrane proteins to lysosomes, photoreceptor degeneration and TRP and Rh1 degradation were prevented. Mass spectrometry analysis showed that only the Sk2-overexpressing flies had a marked accumulation of DHS1P, and feeding DHS1P to wild-type flies or Sk1-overexpressing flies also caused photoreceptor degeneration and decreased abundance of TRP and Rh1. Overexpression of Sk2 in the calx mutant, which is deficient in a calcium exchanger that counters the calcium influx mediated by TRP, suppressed the degeneration phenotype, suggesting that Sk2 alters calcium signaling. Loss-of-function analysis showed that loss of Sk1, but not of Sk2, caused a reduction in the abundance of TRP and Rh1 and an increase in the ratio of DHS1P to S1P. Thus, the authors concluded that Sk1 and Sk2 are partially redundant but exhibit distinct subcellular localizations and have partially selective functions, with Sk2 producing DHS1P, possibly at lysosomes, and thus influencing delivery of plasma membrane cargo to this degradative organelle.

I. Yonamine, T. Bamba, N. K. Nirala, N. Jesmin, T. Kosakowska-Cholody, K. Nagashima, E. Fukusaki, J. K. Acharya, U. Acharya, Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors. J. Cell Biol. 192, 557–567 (2011). [Abstract] [Full Text]