Pic, an Autotransporter Protein Secreted by Different Pathogens in the Enterobacteriaceae Family, Is a Potent Mucus Secretagogue

Abstract

A hallmark of enteroaggregative Escherichia coli (EAEC) infection is a formation of biofilm, which comprises a mucus layer with immersed bacteria in the intestines of patients. While studying the mucinolytic activity of Pic in an in vivo system, rat ileal loops, we surprisingly found that EAEC induced hypersecretion of mucus, which was accompanied by an increase in the number of mucus-containing goblet cells. Interestingly, an isogenic pic mutant (EAEC ⌬pic) was unable to cause this mucus hypersecretion. Furthermore, purified Pic was also able to induce intestinal mucus hypersecretion, and this effect was abolished when Pic was heat denatured. Site-directed mutagenesis of the serine protease catalytic residue of Pic showed that, unlike the mucinolytic activity, secretagogue activity did not depend on this catalytic serine protease motif. Other pathogens harboring the pic gene, such as Shigella flexneri and uropathogenic E. coli (UPEC), also showed results similar to those for EAEC, and construction of isogenic pic mutants of S. flexneri and UPEC confirmed this secretagogue activity. Thus, Pic mucinase is responsible for one of the pathophysiologic features of the diarrhea mediated by EAEC and the mucoid diarrhea induced by S. flexneri.

Infection strategies of enteric pathogenic Escherichia coli

“…53 Conversely, Pic can induce mucus hypersecretion and an increase in the number of mucus-producing goblet cells. 54 Pic has also been implicated in immunomodulation by cleaving leukocyte surface glycoproteins and inducing both activation and apoptosis in T cells, but impaired migration, of polymorphonuclear leukocytes (PMNs). 55 Pet is a well characterized class I SPATE that is endocytosed by host cells, undergoes retrograde trafficking and utilizes the ER-associated degradation (ERAD) pathway to be released into the cytosol.…”

Mecanismos de virulencia de Escherichia coli enteropatógena

“…Pic (grupo no citotóxicos) es una proteasa que incrementa el número de células caliciformes y la producción de moco que atrapa las bacterias auto-aglutinándolas en el epitelio intestinal, aunque su mecanismo de acción aún está en estudio. También es responsable de la actividad mucinolítica que le abre paso a través de esta capa de moco 98 . Pet es una SPATE citotóxica que se une a la espectrina en la membrana del complejo de Golgi, bloquea su función y causa el redondeamiento de la célula 99 .…”

Animal models of enteroaggregativeEscherichia coliinfection

“…49,50 Notably, Pic causes hypersecretion of intestinal mucus in EAEC infected rat ileal loops while also significantly increasing the number of mucus-containing goblet cells in intestinal villi. 51 Moreover, Pic efficiently cleaves extracellular glycoproteins on human leukocytes like CD43, a highly expressed surface marker found on almost all cells from a hematopoietic lineage. Interestingly, Pic protein is a key virulence factor in other enteropathogens including uropathogenic E. coli and Shigella flexneri, underscoring its importance in EAEC pathogenicity.…”