Christopher Vincent Nicchitta

From the ER to Stress Granules: Defining Pathways of RNA Regulation:

Our laboratory investigates how cells control the location and timing of protein synthesis, with a focus on mRNA localization—the process by which mRNAs are targeted to specific sites within the cell to direct protein production. This spatial and temporal regulation is essential for cell signaling, division, and overall cellular dynamics.

We study mRNA localization to the endoplasmic reticulum (ER), where this process occurs on an unusually large scale. While the ER has long been recognized as the translation site for mRNAs encoding secretory and membrane proteins, our research has revealed that the ER functions far more broadly, supporting translation across the transcriptome. In particular, we have shown that newly exported mRNAs are preferentially translated on the ER, a process we hypothesize is coupled to RNA quality-control mechanisms during the pioneer rounds of translation.

Our recent work has also uncovered links between ER-directed mRNA localization and the pathways governing stress granule (SG) biogenesis. We are currently investigating how transcriptional status influences mRNA recruitment into SGs, the mechanisms that determine which mRNAs are selected, and the role of ER-associated sites in organizing SG assembly.

To address these questions, we combine biochemistry, cell biology, advanced imaging, genomics, and computational biology. Current research themes include:

1. Cis-encoded signals and targeting mechanisms – defining mRNA sequence elements and cellular factors that direct ER localization. Beyond the canonical SRP pathway, our CRISPR/Cas studies have revealed additional, pathway-independent routes that recruit even cytosolic and nucleoplasmic mRNAs to the ER.
2. RNA-binding proteins and stress responses – investigating how RNA-binding proteins mediate mRNA localization to the ER and regulate selective mRNA recruitment into SGs. Approaches include optical imaging, nucleoside analog pulse-labeling, cell fractionation, proteomics, ribosome footprinting, and RNA-seq methods (including 4SU-RNAseq).

Through these studies, our goal is to uncover fundamental principles of RNA regulation, quality control, and cellular organization.