Jeff Gerst Research

	Jeff Gerst
Telephone	08-934 2106
Fax	08-934 4108
Office	Room 411 Arthur & Rochelle Belfer Bldg. for Biomedical Research Weizmann Institute of Science Rehovot 76100, Israel
E-mail	jeffrey.gerst@weizmann.ac.il

Protein and mRNA transport in cell growth and disease

Protein localization within the cell is a key determinant of whether cells establish sub-cellular domains necessary for different activities, confer the molecular interactions required for protein function, and create functional organelles. Yet, the mechanisms that determine protein localization at the intracellular level are not well understood and events that lead to the mislocalization of proteins can have dramatic consequences upon cell viability. Our lab studies the role of mRNA and protein transport in a variety of cellular processes, such as organelle biogenesis, polarized growth, and morphogenesis in simple organisms, such as yeast, and in mammalian cells. Two main avenues of investigation are employed.

The first examines the contribution of mRNA trafficking and localized translation to protein localization within cells, and uses live cell imaging, as well as biochemical and genetic approaches to analyze where and how RNAs localize within the cell. We have developed a number of tools to facilitate this work, such as m-TAG, a chromosomal tagging procedure that allows for the visualization of endogenously expressed RNAs in vivo using fluorescent proteins [14,18], or RaPID, which allows for the affinity purification of specific RNAs and subsequent analysis of the bound proteins (i.e. RNA-binding proteins) and cohort RNAs (i.e. RNAs contained within the same ribonucleoprotein particle) [22]. We have used RNA tagging and visualization to show a wide variety of important principles, such as that mRNAs encoding polarity and secretion factors anchor to, and are co-trafficked with, the cortical endoplasmic reticulum to reach polarized cell extensions [13,30].

In addition, we have shown for the first time that ligand-activated RNA trafficking is essential for chemotropism and cell-cell mating [30]. Ongoing studies examine the role of RNA trafficking in peroxisome [20] and mitochondrial [27] biogenesis and function, as well as the mechanisms of RNA targeting to the ER [15,21]. Our work shows that most, if not all, mRNAs are targeted to specific sites within single cells and that the mRNA localizome is an important level of regulation that governs protein localization within cells.

PEX14 mRNA (green fluorescence), which encodes a peroxisomal protein, associates with peroxisomes (red fluorescence) throughout the cell cycle

The second avenue of investigation examines the role of endosomal protein transport in cell growth and the onset of lysosomal storage diseases, such as Batten disease (aka juvenile neuronal ceroid lipofuscinosis, an incurable neurodegenerative disorder). We employ yeast as a model system to understand how orthologs of disease genes work at the molecular level and have shown that the Batten disease gene (e.g. CLN3/BTN1) regulates endosomal transport by controlling a kinase that phosphorylates proteins involved in endosome-Golgi transport steps [28]. This discovery is allowing us to examine endosome-Golgi trafficking in mammalian cells in order to find small molecules that may prove to be of therapeutic benefit. Other findings by our group have shown that Batten disease-related genes in yeast (e.g. Btn2, Btn3) regulate not only endosomal protein sorting, but also the elimination of misfolded protein aggregates (e.g. prions) from cells [12,26]. Together, these works aim to show the role of RNA and protein trafficking in basic cellular functions and how changes therein can lead to the onset of disease in humans.

Research Activities

Protein and mRNA transport in cell growth and disease