Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The reversal of ubiquitination induced by members of the SidE effector family of Legionella pneumophila produces phosphoribosyl ubiquitin (PR-Ub) that is potentially detrimental to host cells. Here we show that the effector LnaB functions to transfer the AMP moiety from ATP to the phosphoryl moiety of PR-Ub to convert it into ADP-ribosylated ubiquitin (ADPR-Ub), which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by Actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (S-HxxxE) present in a large family of toxins from diverse bacterial pathogens. Our study not only reveals intricate mechanisms for a pathogen to maintain ubiquitin homeostasis but also identifies a new family of enzymes capable of protein AMPylation, suggesting that this posttranslational modification is widely used in signaling during host-pathogen interactions.

Pathogen effector AvrSr35 triggers Sr35 resistosome assembly via a direct recognition mechanism.

Nucleotide-binding, leucine-rich repeat receptors (NLRs) perceive pathogen effectors to trigger plant immunity. The direct recognition mechanism of pathogen effectors by coiled-coil NLRs (CNLs) remains unclear. We demonstrate that the Triticum monococcum CNL Sr35 directly recognizes the pathogen effector AvrSr35 from Puccinia graminis f. sp. tritici and report a cryo-electron microscopy structure of Sr35 resistosome and a crystal structure of AvrSr35. We show that AvrSr35 forms homodimers that are disassociated into monomers upon direct recognition by the leucine-rich repeat domain of Sr35, which induces Sr35 resistosome assembly and the subsequent immune response. The first 20 amino-terminal residues of Sr35 are indispensable for immune signaling but not for plasma membrane association. Our findings reveal the direct recognition and activation mechanism of a plant CNL and provide insights into biochemical function of Sr35 resistosome.

Adrenomedullin: an important participant in neurological diseases.

Adrenomedullin, a peptide with multiple physiological functions in nervous system injury and disease, has aroused the interest of researchers. This review summarizes the role of adrenomedullin in neuropathological disorders, including pathological pain, brain injury and nerve regeneration, and their treatment. As a newly characterized pronociceptive mediator, adrenomedullin has been shown to act as an upstream factor in the transmission of noxious information for various types of pathological pain including acute and chronic inflammatory pain, cancer pain, neuropathic pain induced by spinal nerve injury and diabetic neuropathy. Initiation of glia-neuron signaling networks in the peripheral and central nervous system by adrenomedullin is involved in the formation and maintenance of morphine tolerance. Adrenomedullin has been shown to exert a facilitated or neuroprotective effect against brain injury including hemorrhagic or ischemic stroke and traumatic brain injury. Additionally, adrenomedullin can serve as a regulator to promote nerve regeneration in pathological conditions. Therefore, adrenomedullin is an important participant in nervous system diseases.