(De)glutamylation and cell death in Leishmania parasites

Trypanosomatids are flagellated protozoan parasites that are very unusual in terms of cytoskeleton organization but also in terms of cell death. Most of the Trypanosomatid cytoskeleton consists of microtubules, forming different substructures including a subpellicular corset. Oddly, the actin network appears structurally and functionally different from other eukaryotic actins. And Trypanosomatids have an apoptotic phenotype under cell death conditions, but the pathways involved are devoid of key mammal proteins such as caspases or death receptors, and the triggers involved in apoptotic induction remain unknown. In this article, we have studied the role of the post-translational modifications, deglutamylation and polyglutamylation, in Leishmania. We have shown that Leishmania apoptosis was linked to polyglutamylation and hypothesized that the cell survival process autophagy was linked to deglutamylation. A balance seems to be established between polyglutamylation and deglutamylation, with imbalance inducing microtubule or other protein modifications characterizing either cell death if polyglutamylation was prioritized, or the cell survival process of autophagy if deglutamylation was prioritized. This emphasizes the role of post-translational modifications in cell biology, inducing cell death or cell survival of infectious agents. Author summary Leishmania are unique unicellular organisms in terms of cytoskeleton organization and mechanisms of cell death. For example, the major cytoskeletal components of these parasites are microtubules, which form a subpellicular corset. In terms of cell death, an apoptotic phenotype has been characterized in Leishmania but the pathways remain unknown, being devoid of key mammal cell death proteins. In a previous article, we demonstrated that the cytoskeleton of this parasite is extensively glutamylated but, paradoxically, overexpression or inhibition of polyglutamylase expression have limited visible cellular consequences. In this manuscript, we have highlighted the link between polyglutamylation and Leishmania cell death, suggesting the importance of the polyglutamylation/deglutamylation balance in this parasite. Further, we have identified, for the first time in Leishmania, deglutamylases, among which one that, in an original manner, deglutamylates glutamates at branching points but also long glutamate side chains. This work emphasizes the role of post-translational modifications as essential regulators of protein function, not only of mammal cells such as neurons or ciliated/flagellated cells, but also of infectious agents. This work suggests an important and discernible live or diecell death or autophagy balance pathway and the conceptual mechanism that is involved in cellular decision making.