RESUMEN
Chlamydial infection requires the formation of a membrane-bound vacuole, termed the inclusion, that undergoes extensive interactions with select host organelles. The importance of the Inc protein CT229 in the formation and maintenance of the chlamydial inclusion was recently highlighted by studies demonstrating that its absence during infection results in reduced bacterial replication, premature inclusion lysis, and host cell death. Previous reports have indicated that CT229 binds Rab GTPases; however, the physiological implications of this interaction are unknown. Here, we show that CT229 regulates host multivesicular trafficking by recruiting multiple Rab GTPases and their cognate effectors to the inclusion. We demonstrate that CT229 specifically modulates clathrin-coated vesicle trafficking and regulates the trafficking of transferrin and the mannose-6-phosphate receptor, both of which are crucial for proper chlamydial development. This study highlights CT229 as a master regulator of multiple host vesicular trafficking pathways essential for chlamydial infection.
Asunto(s)
Proteínas Bacterianas/metabolismo , Infecciones por Chlamydia/metabolismo , Chlamydia trachomatis/metabolismo , Vesículas Cubiertas por Clatrina/metabolismo , Vacuolas/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Proteínas Bacterianas/genética , Transporte Biológico Activo , Infecciones por Chlamydia/genética , Infecciones por Chlamydia/patología , Chlamydia trachomatis/genética , Vesículas Cubiertas por Clatrina/genética , Vesículas Cubiertas por Clatrina/microbiología , Células HeLa , Humanos , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/microbiología , Vacuolas/genética , Vacuolas/microbiología , Proteínas de Unión al GTP rab/genéticaRESUMEN
Many pathogens hijack existing endocytic trafficking pathways to exert toxic effects in cells. Dynamin controls various steps of the intoxication process used by numerous pathogenic bacteria, viruses, and toxins. Targeting dynamin with pharmaceutical compounds may therefore have prophylactic potential. Here we review the growing number of pathogens requiring dynamin-dependent trafficking to intoxicate cells, outline the mode of internalization that leads to their pathogenicity, and highlight the protective effect of pharmacological and genetic approaches targeting dynamin function. We also assess the methodologies used to investigate the role of dynamin in the intoxication process and discuss the validity and potential pitfalls of using dynamin inhibitors (DIs) as therapeutics.