The requirement of cholesterol for myoblast fusion has been linked to the primary step in the fusion process, calcium-dependent aggregation (recognition). Inhibition of cholesterol synthesis with 25-hydroxycholesterol or compactin in the absence of exogenous lipid dramatically inhibits calcium-mediated aggregation and concomitant fusion within several hours. Restimulating cholesterol synthesis or supplying exogenous cholesterol rapidly restores aggregation activity. Over this time period, however, the sterol:phospholipid ratio is unaltered, suggesting a local rather than a general membrane cholesterol requirement for the expression of aggregation activity. The aggregation response to a change in sterol availability occurs on a shorter time scale than that required to inhibit the synthesis of the protein(s) with aggregation activity; thus, the cholesterol-requiring step is posttranslational. We suggest that the assembly or maintenance of the aggregation activity depends on a continued local supply of cholesterol.

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