Identification of a Chlamydial Protease–Like Activity Factor Responsible for the Degradation of Host Transcription Factors

Abstract

Microbial pathogens have been selected for the capacity to evade or manipulate host responses in order to survive after infection. Chlamydia, an obligate intracellular pathogen and the causative agent for many human diseases, can escape T lymphocyte immune recognition by degrading host transcription factors required for major histocompatibility complex (MHC) antigen expression. We have now identified a chlamydial protease– or proteasome–like activity factor (CPAF) that is secreted into the host cell cytosol and that is both necessary and sufficient for the degradation of host transcription factors RFX5 and upstream stimulation factor 1 (USF-1). The CPAF gene is highly conserved among chlamydial strains, but has no significant overall homology with other known genes. Thus, CPAF represents a unique secreted protein produced by an obligate intracellular bacterial pathogen to interfere with effective host adaptive immunity.

Chlamydia trachomatis Infection Induces Cleavage of the Mitotic Cyclin B1

“…Disruption of this component of the host cytoskeletal network has been postulated to allow the C. trachomatis vacuole to expand during infection. Proteolysis of several of these proteins has been attributed to the activity of CPAF (chlamydial proteasome-like activity factor), a Chlamydia protein that is secreted into the host cell cytosol (39,44). CPAF targets a wide variety host factors for degradation, and it is exciting to speculate that CPAF may also be responsible for the cyclin B1 cleavage observed in C. trachomatis-infected cells.…”

Chlamydia-Infected Cells Continue To Undergo Mitosis and Resist Induction of Apoptosis

“…Based on both our previous studies (16) and the present work, we hypothesize that chlamydiae may secrete factors into host cells for actively blocking host apoptosis pathways. Efforts are under way to identify the potential antiapoptotic factor(s) by using a combination of genetic selection and biochemical purification approaches (52) and to further understand the mechanisms of chlamydial antiapoptotic activity.…”

“…It is known that chlamydia-laden vacuoles can actively avoid fusion with lysosomes, although the molecular mechanism involved remains to be elucidated (21,42). We have previously shown that chlamydiae possess various molecular means for protecting the infected cells from being destroyed by host defense mechanisms, including suppression of host cell major histocompatibility complex antigen expression (52)(53)(54) and blockade of host cell apoptosis pathways (16). However, due to the complex interactions between chlamydiae and host cells, different labs have reported varied outcomes in regard to chlamydial effects on the host apoptosis program.…”

Molecular Mimicry of an HLA-B27-derived Ligand of Arthritis-linked Subtypes with Chlamydial Proteins

“…C. trachomatis has evolved mechanisms to evade CTL recognition and killing of infected cells through degrading the transcription factor RFX5, which is needed for constitutive and IFN-␥-induced MHC class I expression, leading to a severe drop of these molecules from the cell surface 24 h or later after infection (55,56). Despite this, CTL responses can be elicited against C. trachomatis-infected cells (57,58), presumably due to bacterial antigen processing and presentation early after infection.…”