Abstract
The protease GP63 is an important virulence factor of Leishmania parasites. We previously showed that GP63 reaches the perinuclear area of host macrophages and that it directly modifies nuclear translocation of the transcription factors NF-κB and AP-1. Here we describe for the first time, using molecular biology and in-depth proteomic analyses, that GP63 alters the host macrophage nuclear envelope, and impacts on nuclear processes. Our results suggest that GP63 does not appear to use a classical nuclear localization signal common between Leishmania species for import, but degrades nucleoporins, and is responsible for nuclear transport alterations. In the nucleoplasm, GP63 activity accounts for the degradation and mislocalization of proteins involved amongst others in gene expression and in translation. Collectively, our data indicates that Leishmania infection strongly affects nuclear physiology, suggesting that targeting of nuclear physiology may be a strategy beneficial for virulent Leishmania parasites.
Highlights
The protozoan species Leishmania major (L. major) and L. mexicana are the causative agent of the cutaneous form of leishmaniasis, an ulcerative disease with ~1 million new cases reported worldwide annually
Unicellular parasites of the genus Leishmania are the causative agent of leishmaniasis, a disease affecting 12 million people worldwide, mainly in tropical and subtropical regions of the developing world
In this study we discovered that a Leishmania virulence factor, GP63, is able to reach host cell nuclei and affect protein transport from and into the nucleus
Summary
The protozoan species Leishmania major (L. major) and L. mexicana are the causative agent of the cutaneous form of leishmaniasis, an ulcerative disease with ~1 million new cases reported worldwide annually. Leishmania suppresses microbicidal and immune functions of the MF, caused by alterations of signaling pathways [1]. In recent years GP63 was found to be a prerequisite for the activation of host protein tyrosine phosphatases (PTPs), such as SHP-1, PTP1B and TCPTP [3], and for the alteration of transcription factor (TF) function through proteolytic cleavage [4]. GP63-mediated cleavage in the case of the TF AP-1 was shown to occur in the nucleus rather than the cytoplasm revealing that a parasite protease may enter the nucleus via an undefined mechanism [5]
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