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Role of Apolipoproteins L in immunity and disease

Periodic Reporting for period 3 - APOLs (Role of Apolipoproteins L in immunity and disease)

Reporting period: 2018-09-01 to 2020-02-29

"We have discovered that natural variant versions of Apolipoprotein L1 (APOL1) that protect humans against infection by the parasite Trypanosoma rhodesiense (responsible for sleeping sickness) also cause kidney disease. APOL1 is a primate-specific member of the APOL family, the function of which is totally unknown. Based on our findings regarding the effect of APOL1 on trypanosomes as well as the structure and expression characteristics of this family of proteins, we suspected APOLs to play a role in the control of the cell fate in the immune system. Therefore, we have proposed to study this role and also to decipher the mechanism by which APOL1 variants cause kidney disease. In the first part of this work we made the totally unexpected discovery that APOL1 is involved in the control of the podocyte cytoskeleton. We are now focusing this research on the exact mechanism by which APOL1 operates. As far as we can see this could reveal novel aspects regarding the processes involved in the control of cellular dynamics, not only in podocytes but also in other cell types.

This project intends to characterize the function of a family of proteins termed Apolipoproteins L, or in short ""APOLs"". A human member of this family, APOL1, is responsible for protecting humans against infection by some African parasites named Trypanosoma brucei. Two Trypanosoma brucei clones, termed rhodesiense and gambiense, can resist APOL1 and therefore, infect humans causing the sleeping sickness disease.
We discovered in 2010 that many human individuals in Africa possess mutations in their APOL1 gene, termed G1 and G2, which enable them to resist infection by rhodesiense. However, this benefit goes with a cost, as these individuals exhibit a strong probability to develop chronic kidney disease.
We proposed to understand why and how APOL1 mutants trigger kidney disease, and more generally, to understand the function of APOLs.
This is important for society, because the molecular mechanisms of chronic kidney disease are not known, and this disease is frequent and important.
During the first part of the work we discovered that APOLs control the cellular cytoskeleton. We have now identified the mechanism involved in this process. APOLs control factors important for the organization of the actomyosin machinery. APOL1 and APOL3 exhibit inverse effects on these factors. We found that C-terminal variants of APOL1 undergo changes that increase their inhibitory potential. This results in changes of actomyosin of podocytes, presumably at the origin of kidney disease.

This work is currently in the final phase, and we envisage the submission of a paper in the coming months.
If fully verified (our work is not finished yet), our discoveries will have a clear impact on strategies to fight against chronic kidney disease. Moreover, as our current hypothesis relates the function of APOLs to the control of the cytoskeleton and consequently to cellular dynamics, our work could significantly contribute to understand how cells switch from adherence to mobility, which is relevant for the understanding of the metastasis process.