Stressed by a Lov triangle.

His-Asp phosphorylation pathways (also known as two-component systems) enable bacteria (and primitive eukaryotic cells and/or eukaryotic organelles) to make important adaptive decisions in response to fluctuations in intraor extracellular chemical and/or physical conditions. These sensory systems are composed of a dimeric sensor protein, with an input domain and histidine kinase domain (HK), and a response regulator (RR). The HK first autophosphorylates on a conserved histidine residue (His) and subsequently loses the phosphate to an aspartic acid residue (Asp) on the RR receiver domain. While most RRs additionally carry an output domain that is activated by phosphorylation of the aforementioned Asp in the receiver domain, other RRs are single-domain proteins, where phosphorylation modulates their interaction with other proteins (4). His-Asp systems have been appropriated for remarkably diverse adaptive responses in bacterial physiology, ranging from cell cycle progression, morphogenesis, and virulence to adaptation to specific and/or general stress conditions. Most knowledge on general stress response signaling stems from research in two model systems: the Gram-negative gammaproteobacterium Escherichia coli and the Gram-positive member of the Firmicutes Bacillus subtilis. Recently, the sensory pathway of the alphaproteobacterial general stress response has been investigated and the components identified, primarily in the cell cycle model system Caulobacter crescentus and its symbiotic relatives. Here, the PhyK HK and the PhyR RR are responsible for the activation of an alternative EcfG-like sigma factor ( ) through a partner-switching mechanism with the T antagonist NepR (1, 2, 5, 7). Activation of PhyK is triggered by osmotic and oxidative stress and requires a specific Cys residue in the periplasmic domain of PhyK, although the precise mechanism by which PhyK senses the stress remains to be elucidated (11). After accepting a phosphoryl group from PhyK, phosphorylated PhyR (PhyR P) acts as a sigma factor decoy that snatches NepR from the NepRT complex, thus releasing T and enabling the formation of a RNA polymerase holoenzyme (E ) that can then activate transcription of the T regulon (1, 2, 5, 7). Remarkably, the attraction of NepR for PhyR P arises from its infatuation with the -like shape (fold) in the PhyR output domain. Whereas PhyR and NepR homologs have also been identified in other alphaproteobacteria, such as Sinorhizobium meliloti and Bradyrhizobium japonicum, so far a PhyK HK has been characterized only in C. crescentus (11). Complex HK-RR relationships exist in several His-Asp sensory systems. While HK-RRs usually form solitary pairs, they can also lie vertically to form a regulatory cascade composed of sequentially acting HK-RRs. In an act of infidelity, an HK is bedded horizontally to phosphorylate or dephosphorylate an alternative RR. For example, when E. coli is grown in standard aerobic conditions, the expression of the outer membrane porins OmpC and OmpF is regulated by the osmolarity of the medium through the RR OmpR, which usually pairs with EnvZ. However, under anaerobic conditions, expression of OmpC and OmpF is also modulated by the ArcB HK, an anaeroresponsive sensor that can also phosphorylate OmpR, in addition to its usual partner ArcA (12). Recently, similar relationships have surfaced for the E. coli NarXNarL and NarQ-NarP pairs in response to nitrate and nitrite, with NarQ exhibiting similar phosphotransferase activity toward both NarP and NarL, while NarX remains faithful to NarL (13). In B. subtilis, the PhoP-PhoR pair, which responds to phosphate limitation, and the essential YycF-YycG couple, which plays an important role in cell division and cell membrane and cell wall homeostasis, cross these boundaries. In phosphate limitation-induced stationary phase, the sensor kinase PhoR is able to phosphorylate the YycF response regulator, even in the presence of YycG (8). Finally, the HK component of the BceRS sensory system can hook up with the RR protein of the YvcPQ bacitracin resistance system in B. subtilis (17). In this issue of Journal of Bacteriology, Foreman et al. (1a) show that the Caulobacter crescentus LovK HK (featuring a LOV [lightoxygen-voltage sensory domain]) can functionally substitute for the general stress HK PhyK (the primary HK for PhyR), at least when its preferred phosphotransfer partner, LovR, a single-domain RR, is absent. This leads to a model in which LovR dictates whether LovK acts as a phosphatase or a kinase for PhyR in wildtype cells. An increase in LovR concentration drains the phosphate from LovK, which in turn dephosphorylates PhyR, enhancing the attenuation of -dependent transcription through NepR. Foreman et al. also show that transcription of lovK and lovR is under the control of the E T (and PhyK-PhyR) and, therefore, that activation of this pathway determines an increase in the levels of LovK and LovR, which in turn attenuates PhyK-PhyRT signaling. However, under conditions in which LovR is absent (or present at low levels), LovK seems to transfer phosphate from its HK domain to PhyR, thus increasing the expression of -dependent genes independently from PhyK (Fig. 1A). This relationship between a single-domain RR, two HK phosphatases and an RR with receiver and output domains is reminiscent of what happens between the members of the DivK-DivJPleC-PleD developmental phosphosignaling system in the same organism (Fig. 1B). In this case, DivK is a single-domain RR able to stimulate the autokinase activity of both DivJ and PleC, and it is essential to switch PleC from its phosphatase to its autokinase activity during differentiation (14). PleC is an active DivK phosphatase at the new cell pole, whereas DivK and PleD compete for