Peptidase Inhibitor 15 (PI15) Regulates Chlamydial CPAF Activity.

Bhupesh K Prusty,Thomas Rudel,Suvagata R Chowdhury,Nitish Gulve

doi:10.3389/fcimb.2018.00183

Bhupesh K Prusty, Thomas Rudel + Show 2 more

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https://doi.org/10.3389/fcimb.2018.00183

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Abstract

Obligate intracellular pathogenic Chlamydia trachomatis express several serine proteases whose roles in chlamydial development and pathogenicity are not completely understood. The chlamydial protease CPAF is expressed during the replicative phase of the chlamydial developmental cycle and is secreted into the lumen of the Chlamydia-containing vacuole called inclusion. How the secreted protease is activated in the inclusion lumen is currently not fully understood. We have identified human serine peptidase inhibitor PI15 as a potential host factor involved in the regulation of CPAF activation. Silencing expression as well as over expression of PI15 affected normal development of Chlamydia. PI15 was transported into the chlamydial inclusion lumen where it co-localized with CPAF aggregates. We show that PI15 binds to the CPAF zymogen and potentially induces CPAF protease activity at low concentrations. However, at high concentrations PI15 inhibits CPAF activity possibly by blocking its protease domain. Our findings shed light on a new aspect of chlamydial host co-evolution which involves the recruitment of host cell proteins into the inclusion to control the activation of bacterial proteases like CPAF that are important for the normal development of Chlamydia.

Highlights

Chlamydia trachomatis is an obligate intracellular pathogen, which causes the eye disease trachoma and different sexually transmitted diseases
To identify host factors that might influence chlamydial growth in presence of human herpesvirus 6 (HHV-6), we performed a microarray based host cell transcriptome analysis and found PI15 to be differentially regulated during Chlamydia and HHV-6 infection (Figure 1A)
Chlamydial Chlamydial Protease-Like Activity Factor (CPAF) is a highly active serine protease that is expressed from the mid-term to the end of the chlamydial developmental cycle

Summary

Introduction

Chlamydia trachomatis is an obligate intracellular pathogen, which causes the eye disease trachoma and different sexually transmitted diseases. Chlamydial proteins secreted via the bacterial type II secretion system including secreted proteases are kept within the inclusion and away from host cell cytoplasm, release of such factors into the host cell cytosol has been suggested to occur during the late stage of the developmental cycle (Chen et al, 2010b) One such widely studied chlamydial protease is Chlamydial Protease-Like Activity Factor (CPAF), which has initially been shown to cleave numerous host cell proteins in infected cells (Pirbhai et al, 2006; Chen et al, 2009; Christian et al, 2010; Jorgensen et al, 2011; Snavely et al, 2014; Tang et al, 2015). Most of these CPAF targets turned out to be cleaved during cell lysis and not in intact cells (Chen et al, 2012)

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