Mechanisms ensuring precise regulation of Lon proteases in bacteria

Intracellular proteolysis underpins a plethora of biological processes and is carried out by highly conserved proteases.

To avoid deleterious and wasteful non-specific protein degradation, proteases must be precisely controlled and highly selective in choosing their substrate proteins.

Despite many years of research on cellular proteases, the precise mechanisms regulating protease activity and specificity remain unclear.

This research project will address these knowledge gaps by focusing on the family of Lon proteases that has members in the three domains of life.

By studying Lon proteases in the α-proteobacterium Caulobacter crescentus and the opportunistic pathogen Pseudomonas aeruginosa, this project will uncover the mechanisms by which two recently discovered regulator proteins tune Lon proteolysis under distinct stress conditions. Additionally, experiments are proposed to define the sequence and structural features governing Lon specificity.

Given Lon’s central role in bacterial physiology, our work will shed light onto the regulation of a variety cellular processes, including bacterial antibiotic tolerance and pathogenicity.

Furthermore, it will promote the development of engineered degradation systems that can be utilized to selectively remove proteins of choice.

Since Lon proteases are promising drug targets, this project will also propel research towards targeting Lon for therapeutic purposes.