Periodic Reporting for period 4 - APOLs (Role of Apolipoproteins L in immunity and disease) Período documentado: 2020-03-01 hasta 2021-06-30 Resumen del contexto y de los objetivos generales del proyecto This project intends to characterize the function of a family of proteins termed Apolipoproteins L, or in short "APOLs". In 2003 my laboratory discovered that a human specific member of this family, APOL1, is responsible for protecting humans against infection by the African parasite Trypanosoma brucei, agent of the Nagana disease in cattle. Two Trypanosoma brucei clones, termed rhodesiense and gambiense, can resist APOL1 and therefore, infect humans causing the sleeping sickness disease. In 2010 we discovered that many human individuals in Africa possess mutations in their APOL1 gene, termed G1 and G2, which enable them to resist infection by Trypanosoma rhodesiense. However, this benefit goes with a cost, as these individuals exhibit a strong probability to develop chronic kidney disease, particularly linked with viral infection.Based on our findings regarding the effect of APOL1 on trypanosomes as well as the structure and expression characteristics of this family of proteins, notably the strong increase of APOLs expression under inflammatory conditions, 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 to decipher the mechanism by which APOL1 variants cause kidney disease. In this work, we made the totally unexpected discovery that APOL1 and APOL3 are involved in the control of the podocyte cytoskeleton, through their ability to regulate the fission and fusion of intracellular membranes. Therefore, our research revealed novel aspects regarding the processes affecting cellular dynamics such as secretion, exocytosis and autophagy, not only in podocytes but also in other cell types. I believe that understanding the function of APOLs is important for society, because the molecular mechanisms of chronic kidney disease are not known. Moreover, as proposed in my 2021 review on the role of APOLs, these proteins could also play an important role in neurotransmission diseases and cancer. Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha We discovered that APOLs are associated with two key factors controlling the cellular cytoskeleton, namely the phosphatidylinositol-4-phosphate kinase IIIB (PI4KB) and the non-muscular myosin 2A (NM2A). Through interaction with these factors, APOL3 control the activity of the actomyosin machinery, particularly for the fission and fusion in intracellular membranes, processes that are involved in vesicular secretion and autophagy. We found that C-terminal variants of APOL1, such as G1 and G2, undergo structural changes that increase the interaction of APOL1 with APOL3, inhibiting the stimulating effect of APOL3 on PI4KB. This results in changes of actomyosin of podocytes, presumably at the origin of kidney disease. Our results also provided an explanation for the linkage between kidney disease and viral infection: through their effect on autophagy, the APOL1 variants hinder autophagy-mediated repair of damages due to infection. Consequently, in 2020 I was the first to propose a mechanism for APOL1-linked kidney disease, in the two top journals in the field of nephrology (Journal of the American Society of Nephrology and Kidney International). Moreover, in 2021 I published a comprehensive and unique review on the function of APOLs, largely based on the results obtained with my ERC grant. Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha) 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 metastasis. Finally, the involvement of APOLs in membrane fission should affect neurotransmission, opening new perspectives in this field. Pays,2020, The mechanism of kidney disease due to APOL1 risk variants. J.Am.Soc. Nephrol,31, 2502
