A. Wali Karzai

Research Interests:

Post-transcriptional Regulation of Gene Expression and Bacterial Pathogenesis

Post-transcriptional regulatory events play a crucial role in controlling gene expression. Our research aims to elucidate post-transcriptional gene regulatory processes, with particular emphasis on investigating: (1) molecular mechanisms that govern protein translation quality control, (2) molecular mechanisms by which RNases and small non-coding RNAs (ncRNAs) target specific substrates and regulate the balance of mRNA decoding, stability and decay, and (3) biochemical mechanism of directed proteolysis and how general proteases are recruited to specific substrates. We are particularly interested in how these post-transcriptional processes (protein synthesis, protein degradation, and mRNA decay) are integrated to achieve a high level of processing efficiency. We use a combination of protein biochemistry, functional genomics, bioinformatics, and structural approaches to determine the biological function and the mechanism of action of RNA-protein and protein-protein complexes.

One of the most fascinating post-transcriptional gene regulatory processes involves tmRNA, also known as SsrA or 10Sa RNA. tmRNA is a highly conserved and versatile molecule endowed with the combined structural and functional properties of both a tRNA and an mRNA. tmRNA, along with its protein cofactors, orchestrates three key biological functions: 1) recognition and rescue of ribosomes stalled on aberrant mRNAs, 2) selective disposal of the causative defective mRNAs, and 3) addition of a degradation tag to ribosome-associated protein fragments for directed proteolysis. Although not essential in E. coli, tmRNA activity is essential for bacterial survival under adverse conditions and for virulence in some, and perhaps all, pathogenic bacteria. Recent evidence suggests that in addition to its quality control function the tmRNA system might also play a key regulatory role in certain physiological pathways.

Our research endeavors are aimed at gaining a thorough and detailed mechanistic understanding of the tmRNA mediated trans-translation process. We have identified a number of key protein factors that play essential roles at distinct steps of the ­trans-translation process. Our future plans are to gain further mechanistic insights into how stalled ribosomes are recognized and rescued, how defective mRNAs are selectively degraded, and how tmRNA tagged proteins are targeted for proteolysis. We are also interested in exploring the physiological significance of the SmpB-tmRNA system. More specifically, we are interested in understanding why the SmpB-tmRNA system is so highly conserved, what selective advantage it confers, and what role(s) it plays in bacterial fitness, survival and pathogenesis.