1) ER Stress. An important stress that the cell has to monitor and regulate is endoplasmic reticulum stress (ER stress), which can be induced by the accumulation of unfolded proteins in the ER. Major secretory cells such as liver and pancreatic beta cells have to tightly monitor the load of secretory proteins within the ER and to ensure that these proteins are folded properly. The accumulation of unfolded proteins in the ER leads to a cellular stress response called the unfolded protein response (UPR). The loss of the UPR or severe ER stress can result in cell death and has been strongly linked to diabetes. One major arm of the UPR results in global translational inhibition, which prevents the accumulation of unfolded proteins in the ER. Although the majority of mRNAs are translationally repressed, it is apparent that a subset of mRNAs is still translated and that these translated mRNAs encode for proteins that are important for cellular survival during ER stress. Our lab is interested in 1) identification of these mRNAs and 2) elucidating their mechanism of gene expression during ER stress. By characterizing these fundamental translational mechanisms, we will have a more complete understanding of the regulations that go awry during disease such as diabetes.

2) Translation. Most messenger RNAs (mRNAs) utilize a cap-dependent scanning mechanism to recruit the ribosome to the mRNA and to set the translating reading frame at the AUG start codon. This pathway requires a complex set of canonical initiation factors that coordinately recruit the ribosome to the mRNA. During cellular stress and viral infection when global translation is repressed, the function of a subset of initiation factors is repressed through post-translational modifications (ie. phosphorylation or cleavage). However, a subset of mRNAs can bypass this translation block. Another major interest in the lab is the study of mRNAs that can be translated during cellular stress and viral infection. Viruses provide an excellent model for understanding these mechanisms as they have evolved clever non-canonical mechanisms to preferentially hijack the ribosome. One particular mechanism is via an internal ribosome entry site (IRES), which are RNA elements that can recruit ribosomes directly to the mRNA using a subset of initiation factors. We are specifically interested in an IRES within the cricket paralysis virus (CrPV). This IRES mimics a tRNA to directly recruit and manipulate the ribosome. Moreover, the IRES does not initiate at the canonical start AUG codon but instead initiates translation at a GCU alanine codon. We are interested in the mechanistic details of how this IRES interacts with and manipulates the ribosome. Because this IRES is functional in many systems including insect cells, yeast and human cells, this suggests that this IRES mechanism is conserved and we hypothesize that the virus usurped this mechanism from the host. Thus, there may be cellular mRNAs that may contain CrPV IRES-like properties. We are keen to identify these mRNAs and to understand their mechanism of action.

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