Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy

Teemu P. Miettinen, and Mikael Björklund

 Cell Rep. 2015 Dec 22;13(11):2610-20.

Speaker: Yin-Ping Wang (王尹平)                               Time: 14:00~15:00, Apr. 06, 2016

Commentator: Dr. Yee-Shin Lin (林以行 教授)         Place: Room 601

Abstract:

Cell size homeostasis is regulated by cell growth and proliferation. It is recognized that prolonged cell division contributes to increasing cell size, because cells have more time to accumulate mass. Loss of homeostatic control of size contributes to various diseases including cancer, neurodegenerative diseases and atrophy (1). However, little is known about how metabolic pathway involved in the cell size homeostasis. The author performed a library screen of 786 FDA-approved drugs and found statins as a cell size regulator. Statins are inhibitors of the mevalonate pathway, an important metabolic pathway involving cholesterol production, structure of cellular membrane and post-translational modification of proteins. Flow cytometry analysis revealed that statins increased cell size with reduced proliferation. Unexpectedly, cellular protein density was also increased, although the intracellular density is considered to be constant in different-size cells (2). To understand the role of the mevalonate pathway in cell size modulation, systematic inhibitions of the pathway by chemical molecules and siRNAs were performed, and geranylgeranylation was further determined to mediate cell size and proliferation effects. Since the inhibition of Rab Geranylgeranyltransferase (RABGGTA) induced significant changes of cell size, the author hypothesized that statin-induced effects on cell size, proliferation and protein density are due to Rab protein prenylation. Through RNA screening, Rab11, a small GTPase required for autophagosome formation, was identified as a main regulator of cell size, and autophagy also played a role in proteostasis. In summary, mevalonate pathway regulates cell size and protein density through proliferation and autophagy via the geranylgeranylation of Rab11.

References:

1.         Lloyd, A.C. (2013). The regulation of cell size. Cell 154, 1194-1205.

2.         Feijo Delgado, F., Cermak, N., Hecht, V.C., Son, S., Li, Y., Knudsen, S.M., Olcum, S., Higgins, J.M., Chen, J., Grover, W.H., et al. (2013). Intracellular water exchange for measuring the dry mass, water mass and changes in chemical composition of living cells. PloS one 8, e67590.