Abstract
In this report, we demonstrate the existence of the ubiquitin fold modifier-1 (Ufm1) and its conjugation pathway in trypanosomatid parasite Leishmania donovani. LdUfm1 is activated by E1-like enzyme LdUba5. LdUfc1 (E2) specifically interacted with LdUfm1 and LdUba5 to conjugate LdUfm1 to proteinaceous targets. Mass spectrometry analysis revealed that LdUfm1 is conjugated to Leishmania protein targets that are associated with mitochondria. Immunofluorescence experiments showed that Leishmania Ufm1, Uba5 and Ufc1 are associated with the mitochondria. The demonstration that all the components of this system as well as the substrates are associated with mitochondrion suggests it may have physiological roles not yet described in any other organism. Overexpression of a non-conjugatable form of LdUfm1 and an active site mutant of LdUba5 resulted in reduced survival of Leishmania in the macrophage. Since mitochondrial activities are developmentally regulated in the life cycle of trypanosomatids, Ufm1 mediated modifications of mitochondrial proteins may be important in such regulation. Thus, Ufm1 conjugation pathway in Leishmania could be explored as a potential drug target in the control of Leishmaniasis.
Highlights
Leishmaniasis is a spectrum of diseases caused by protozoan parasites belonging to several different Leishmania species
In this report we demonstrated the existence of an ubiquitin fold modifier-1 (Ufm1) conjugation pathway in the human protozoan parasite Leishmania donovani including the enzymatic steps involving activation by
All the components of Ufm1 conjugation and the substrate proteins in Leishmania appear to be associated with the mitochondria
Summary
Leishmaniasis is a spectrum of diseases caused by protozoan parasites belonging to several different Leishmania species. These blood borne pathogens are currently prevalent in 88 countries around the World with an estimated 2 million new cases each year [1]. In addition to initiation of transcription and posttranscriptional changes, a wide range of post-translational modifications are known to occur in eukaryotic cells These modifications greatly expand the functional diversity of the proteome. Apart from ubiquitin, a growing list of small ubiquitin like proteins called Ubls is being discovered [4] These Ubls possess essentially the same three dimensional structures as ubiquitin and employ mechanisms that generally follow the ubiquitin prototype for conjugation to protein substrates. These Ubls regulate a variety of biological functions ranging from endocytosis, membrane trafficking, protein kinase activation, DNA repair and chromatin dynamics [5,6]
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