A Radical Reimagining of Fungal Two-Component Regulatory Systems

Bacterial two-component regulatory systems (TCSs) mediate signal transduction by transferring phosphoryl groups between sensor kinase and response regulator proteins, sometimes using intermediary histidine-phosphotransferase (Hpt) domains to form multistep phosphorelays. Because (i) almost all known fungal sensor kinases exhibit a domain architecture characteristic of bacterial TCS phosphorelays, (ii) all known fungal Hpts are stand-alone proteins suited to shuttle between cytoplasm and nucleus, and (iii) the best-characterized fungal TCS is a canonical phosphorelay, it is widely assumed that most or all fungal TCSs function via phosphorelays. However, fungi generally encode more sensor kinases than Hpts or response regulators, leading to a disparity between putative phosphorelay inputs and outputs. The simplest resolution of this paradox is to hypothesize that most fungal sensor kinases do not participate in phosphorelays. Reimagining how fungal TCSs might function leads to multiple testable predictions.