BRC-BIO: Investigation of the tissue-specific role of the ER membrane protein complex (EMC) in the development and maintenance of a multicellular organism

Cells require many proteins, either embedded in the cellular membrane or moved outside of the cell via small packages, for numerous processes. These proteins can serve a variety of essential functions, such as receptors, tethers, and signals to other cells. These proteins typically are particularly challenging to fold into the correct shape.

The endoplasmic reticulum (ER) is the location where this processing occurs with the help of specialized protein complexes. The PI and undergraduate researchers recently found that loss of one component of an ER membrane protein complex, EMC4, in specialized cells of the nervous system called glia, led to a shortened lifespan, locomotor deficits, and other detrimental outcomes in the model organism, the fruit fly.

The proposed research will investigate novel questions regarding (1) when during the life cycle is this component required for organismal health, (2) which types of cells in the nervous system require this component to function normally, and (3) what is the role of other members of this ER membrane protein complex. Answering these questions will provide insight into how the ER processes proteins and whether this differs between specialized cell types or life stages of an organism.

This project will provide scientific training to Lake Forest College undergraduates through mentored research experiences, improving their access to and preparation for STEM careers. The proposed project will also incorporate a multi-year Course-Based Undergraduate Research Experience (CURE) to significantly increase the number of students that gain valuable research training.

The recently discovered ER membrane protein complex (EMC) consists of 8-10 conserved subunits, and is thought to be involved in insertion, folding, and protection from degradation of membrane proteins. However, understanding of EMC function is limited by the fact that most prior work has been conducted in single-cell systems. A multicellular organism is required to investigate the cell type-specific roles of EMC subunits or the impact of EMC function on different life stages.

Drosophila represent a powerful model system to answer questions that integrate the molecular and cellular function of EMC with its impact on the organism. The PI and undergraduate researchers recently discovered that glia-specific RNAi knockdown (KD) of the fly homolog of an EMC subunit, EMC4, severely reduces adult survival. Flies lacking glial expression of EMC4 also display a mild developmental delay, but no significant decrease in developmental viability.

EMC4 glial KD flies also display severe locomotor defects and increased protein aggregation. This research proposes to investigate (1) the role that glial EMC4 plays in different life stages, specifically during development vs. during maintenance of an adult organism, (2) the cell-specific function of EMC4 in specialized cell types of the nervous system, and (3) the specificity of any of these phenotypes to EMC4 vs. other EMC subunits.

This research will advance understanding of the role of EMC in membrane protein biogenesis by taking an integrative approach examining survival, behavior, and development alongside molecular and cellular function.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.