Tuesday, May 7, 2013

Notes on Gebre12, Osh6 overexpression extends yeast replicative lifespan

Gebre et al 2012, Cell Cycle, OSH6 overexpression extends yeast lifespan.  Paper from Fusheng Tang's group.

There 7 oxysterol binding proteins in yeast. Deletion of OSH5 and OSH6 upregulated mRNAs of ERG8 and ERG9. Overexpression OSH6 down-regulate total cellular sterol levels.

So, I figure that normal function of OSH6 should inhibits ERG9. Because ergosterol reduce membrane fluidity, so OSH6 normally increase membrane fluidity.
                 OSH6 ---| ERG9 ---| membrane fluidity ---> lifespan
This scheme is consistent with Gebre12's observation that over-expression of OSH6 can rescue vacuole fragmentation. Because over-expression of OSH6 extend lifespan, so its normal function should also 'extend' lifespan (similar to overexpression effect of SIR2). This seems to suggest that membrane fluidity is good for replicative lifespan, and it seems to make sense that more fluid cell membrane lead to more buddings.

Gebre12 used the ERG6 promoter to over-express OSH6,  OSH5, and perhaps other OSH genes. 

Question: OSH6 and OSH7 are paralogs, based on SGD. Gebre12 stated that they screened OSH genes and found OSH6 when overexpressed can complement vacuole fragmentation. How about OSH7?

Another question: How does ergosterol influence cellular membrane? Because ergosterol is the cholesterol in yeast, ergosterol should improve the rigidity of cellular membrane.
 Quote from Wikipedia on Cholesterol:
Cholesterol is required to build and maintain membranes; it modulates membrane fluidity over the range of physiological temperatures. The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which reduces membrane fluidity.[11] The structure of the tetracyclic ring of cholesterol contributes to the decreased fluidity of the cell membrane as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar.[12] In this structural role, cholesterol reduces the permeability of the plasma membrane to neutral solutes,[13] protons, (positive hydrogen ions) and sodium ions.[14]
Question: Do overexpression of other OSH genes have no effect on lifespan? They probably did not extend lifespan, and only PERG6-OSH6 extend lifespan.

Figure2 provides survival curves of WT,  PERG6-OSH6, and PERG6-OSH5.  All 3 survival curves seems to have simliar Gompertz coefficient but different initial mortality rates. When different domains are chopped off from OSH6, the Gompertz coefficients of survivals are changed (Figure 3B). 

Interestingly, PERG-OSH6 is sensitive to rapamycin, and can not only abolish the lifespan extension effect of tor1Delta, but even reverse the effect of tor1Delta (Figure 6A and 6B).

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