Chlamydial protease CT441 interacts with SRAP1 co-activator of estrogen receptor alpha and partially alleviates its co-activation activity.

Chlamydiae are obligate intracellular pathogens which secrete host-interactive proteins capable of directly modulating eukaryotic pathways. Using the PDZ domain of the protease CT441 of Chlamydia trachomatis as a bait in a yeast two-hybrid screen, we identified the SRAP1 co-activator of estrogen receptor alpha (ERalpha) as an interacting protein. SRAP1 is a unique modulator of steroid receptor activity, as it is able to mediate its co-regulatory effects both as a RNA and a protein. GST pull-down experiments confirmed the interaction of CT441 and SRAP1 in vitro. Furthermore, it was shown that the CT441-PDZ domain fused to a nuclear localization signal was able to bind and to target SRAP1 to the nucleus in mammalian cells. CT441 did not cleave SRAP1, but retained the protein in the cytoplasm and thereby partially alleviated its co-activation of ERalpha in a heterologous yeast system and in mammalian cells. Possible implications of chlamydial regulation of host metabolism by targeting ERalpha activity are discussed. Moreover, the property of CT441-PDZ domain to specifically sequester SRA1 protein but not SRA1 RNA may be used to distinguish between the cellular functions of the SRA1 RNA and protein. This has clinical relevance as it has been proposed that disturbance of the balance between SRAP1-coding and non-coding SRA1 RNAs in breast tumor tissues might be involved in breast tumorigenesis.