The Circulating Protease Persephone Is an Immune Sensor for Microbial Proteolytic Activities Upstream of the Drosophila Toll Pathway

• Published in: Molecular cell 2018-02, Vol.69 (4), p.539-550.e6
• Main Authors: Issa, Najwa, Guillaumot, Nina, Lauret, Emilie, Matt, Nicolas, Schaeffer-Reiss, Christine, Van Dorsselaer, Alain, Reichhart, Jean-Marc, Veillard, Florian
• Format: Article
• Language: English
• Subjects: Animals; bacterial proteases; Beauveria - enzymology; cathepsin 26-29-p; Chemical Sciences; clip-serine protease; cysteine cathepsin; danger signal; Drosophila melanogaster - enzymology; Drosophila melanogaster - growth & development; Drosophila melanogaster - immunology; Drosophila Proteins - immunology; Drosophila Proteins - metabolism; Female; fungal proteases; immune receptor; Immunity, Innate - immunology; innate immunity; Male; NF-κB pathway; Proteolysis; Receptors, Immunologic - metabolism; Serine Endopeptidases - immunology; Serine Endopeptidases - metabolism; Serine Proteases - immunology; Serine Proteases - metabolism; Signal Transduction; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; virulence factors
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.01.029

Microbial or endogenous molecular patterns as well as pathogen functional features can activate innate immune systems. Whereas detection of infection by pattern recognition receptors has been investigated in details, sensing of virulence factors activities remains less characterized. In Drosophila, genetic evidences indicate that the serine protease Persephone belongs to a danger pathway activated by abnormal proteolytic activities to induce Toll signaling. However, neither the activation mechanism of this pathway nor its specificity has been determined. Here, we identify a unique region in the pro-domain of Persephone that functions as bait for exogenous proteases independently of their origin, type, or specificity. Cleavage in this bait region constitutes the first step of a sequential activation and licenses the subsequent maturation of Persephone to the endogenous cysteine cathepsin 26-29-p. Our results establish Persephone itself as an immune receptor able to sense a broad range of microbes through virulence factor activities rather than molecular patterns. [Display omitted] •All pathogen-secreted proteases activate the danger-sensing arm of the Toll pathway•The protease Persephone is the immune sensor for microbial proteolytic activities•A sensitive region in Persephone zymogen functions as a bait for exogenous proteases•Bait-region hydrolysis primes maturation of Persephone by the host cathepsin 26-29-p Innate immune systems are activated by microbial molecular patterns or pathogen functional features. Issa et al. show that the Drosophila Toll pathway senses pathogen proteases through a hydrolysis-sensitive region localized in the Persephone pro-domain. Cleavage of this bait region primes maturation of Persephone and activation of the pathway by the host cathepsin 26-29-p.