Apolipoprotein-L Functions in Membrane Remodeling.

The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some of which are involved in the control of membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 and APOL3 appear to control membrane remodeling linked to pathogen infection. Through its association with Non-Muscular Myosin-2A (NM2A), APOL1 controls Golgi-derived trafficking of vesicles carrying the lipid scramblase Autophagy-9A (ATG9A).

Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease.

Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills through induction of apoptotic-like parasite death, but two clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones.

The Janus-faced functions of Apolipoproteins L in membrane dynamics.

The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis of bloodstream trypanosomes and intracellular bacteria, modulation of viral infection and induction of apoptosis, autophagy, and chronic kidney disease. Based on recent work, I propose that the basic function of APOLs is the control of membrane dynamics, at least in the Golgi and mitochondrion. Together with neuronal calcium sensor-1 (NCS1) and calneuron-1 (CALN1), APOL3 controls the activity of phosphatidylinositol-4-kinase-IIIB (PI4KB), involved in both Golgi and mitochondrion membrane fission.

Apolipoproteins L1 and L3 control mitochondrial membrane dynamics.

Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1.

The Pathogenesis of African Trypanosomiasis.

African trypanosomes are bloodstream protozoan parasites that infect mammals including humans, where they cause sleeping sickness. Long-lasting infection is required to favor parasite transmission between hosts. Therefore, trypanosomes have developed strategies to continuously escape innate and adaptive responses of the immune system, while also preventing premature death of the host.

Distinct APOL1 functions in trypanosomes and kidney podocytes.

The human serum protein apolipoprotein L1 (APOL1) kills Trypanosoma brucei but not the sleeping sickness agent Trypanosoma rhodesiense. APOL1 C-terminal variants can kill T. rhodesiense but they also induce kidney disease.

Genetic and immunological basis of human African trypanosomiasis.

Human African trypanosomiasis, or sleeping sickness, results from infection by two subspecies of the protozoan flagellate parasite Trypanosoma brucei, termed Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, prevalent in western and eastern Africa respectively. These subspecies escape the trypanolytic potential of human serum, which efficiently acts against the prototype species Trypanosoma brucei brucei, responsible for the Nagana disease in cattle. We review the various strategies and components used by trypanosomes to counteract the immune defences of their host, highlighting the adaptive genomic evolution that occurred in both parasite and host to take the lead in this battle.

The KIFC1 Kinesin Ensures the Fast Antibody Clearance Required for Parasite Infectivity.

Human innate immunity to involves the trypanosome C-terminal kinesin KIFC1, which transports internalized trypanolytic factor apolipoprotein L1 (APOL1) within the parasite. We show that KIFC1 preferentially associates with cholesterol-containing membranes and is indispensable for mammalian infectivity. Knockdown of KIFC1 did not affect trypanosome growth but rendered the parasites unable to infect mice unless antibody synthesis was compromised.

Multiparametric Atomic Force Microscopy Identifies Multiple Structural and Physical Heterogeneities on the Surface of .

A unique feature of the African trypanosome is the presence of an outer layer made of densely packed variable surface glycoproteins (VSGs), which enables the cells to survive in the bloodstream. Although the VSG coat is critical to pathogenesis, how exactly the glycoproteins are organized at the nanoscale is poorly understood. Here, we show that multiparametric atomic force microscopy is a powerful nanoimaging tool for the structural and mechanical characterization of trypanosomes, in a label-free manner and in buffer solution.

The function of apolipoproteins L (APOLs): relevance for kidney disease, neurotransmission disorders, cancer and viral infection.

The discovery that apolipoprotein L1 (APOL1) is the trypanolytic factor of human serum raised interest about the function of APOLs, especially following the unexpected finding that in addition to their protective action against sleeping sickness, APOL1 C-terminal variants also cause kidney disease. Based on the analysis of the structure and trypanolytic activity of APOL1, it was proposed that APOLs could function as ion channels of intracellular membranes and be involved in mechanisms triggering programmed cell death. In this review, the recent finding that APOL1 and APOL3 inversely control the synthesis of phosphatidylinositol-4-phosphate (PI(4)P) by the Golgi PI(4)-kinase IIIB (PI4KB) is commented.

APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin.

The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB).

Identification and preliminary characterization of a putative C-type lectin receptor-like protein in the T. cruzi tomato lectin endocytic-enriched proteome.

Trypanosoma cruzi, the etiological agent of the Chagas' disease in Latin America undergoes a complex life cycle involving two hosts, a mammalian host and a reduviid insect vector (triatomine). In the insect midgut the parasite multiplies as epimastigote forms, which rely on endocytosis for their energy requirement. We recently showed that posttranslational modification of endocytic N-glycoproteins by tomato lectin (TL) binding-N-glycans is crucial for receptor-mediated endocytosis (RME) in epimastigote forms.

APOLs with low pH dependence can kill all African trypanosomes.

The primate-specific serum protein apolipoprotein L1 (APOL1) is the only secreted member of a family of cell death promoting proteins . APOL1 kills the bloodstream parasite Trypanosoma brucei brucei, but not the human sleeping sickness agents T.b.

Infection in Mice Critically Relies on Mannose Receptor-Mediated Arginase Induction by a KHC1 Kinesin H Chain Homolog.

Arginase activity induction in macrophages is an escape mechanism developed by parasites to cope with the host's immune defense and benefit from increased host-derived growth factor production. We report that arginase expression and activity were induced in macrophages during mouse infection by , a natural parasite of this host. This induction was reproduced in vitro by excreted/secreted factors of the parasite.

Trypanosoma brucei growth control by TNF in mammalian host is independent of the soluble form of the cytokine.

Infection of C57Bl/6 mice by pleomorphic African trypanosomes Trypanosoma brucei and T. congolense is characterized by parasitemia waves coupled with the production of systemic levels of TNF. This cytokine is known to control T.

Specific Endocytosis Blockade of Trypanosoma cruzi Exposed to a Poly-LAcNAc Binding Lectin Suggests that Lectin-Sugar Interactions Participate to Receptor-Mediated Endocytosis.

Trypanosoma cruzi is a protozoan parasite transmitted by a triatomine insect, and causing human Chagas disease in South America. This parasite undergoes a complex life cycle alternating between non-proliferative and dividing forms. Owing to their high energy requirement, replicative epimastigotes of the insect midgut display high endocytic activity.

Apolipoproteins L control cell death triggered by TLR3/TRIF signaling in dendritic cells.

Apolipoproteins L (ApoLs) are Bcl-2-like proteins expressed under inflammatory conditions in myeloid and endothelial cells. We found that Toll-like receptor (TLR) stimuli, particularly the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), specifically induce ApoLs7/11 subfamilies in murine CD8α(+)  dendritic cells (DCs). This induction requires the TLR3/TRIF (where TRIF is TIR domain containing adapter-inducing interferon β) signaling pathway and is dependent on IFN-β in all ApoLs subfamilies except for ApoL7c.

Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection.

Unlabelled: African trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can resist human ApoL1 because they express the serum resistance proteins T. b.

Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1.

Humans resist infection by the African parasite Trypanosoma brucei owing to the trypanolytic activity of the serum apolipoprotein L1 (APOL1). Following uptake by endocytosis in the parasite, APOL1 forms pores in endolysosomal membranes and triggers lysosome swelling. Here we show that APOL1 induces both lysosomal and mitochondrial membrane permeabilization (LMP and MMP).

Sequencing rare and common APOL1 coding variants to determine kidney disease risk.

A third of African Americans with sporadic focal segmental glomerulosclerosis (FSGS) or HIV-associated nephropathy (HIVAN) do not carry APOL1 renal risk genotypes. This raises the possibility that other APOL1 variants may contribute to kidney disease. To address this question, we sequenced all APOL1 exons in 1437 Americans of African and European descent, including 464 patients with biopsy-proven FSGS/HIVAN.

Adaptation of Trypanosoma rhodesiense to hypohaptoglobinaemic serum requires transcription of the APOL1 resistance gene in a RNA polymerase I locus.

Human apolipoprotein L1 (APOL1) kills African trypanosomes except Trypanosoma rhodesiense and Trypanosoma gambiense, the parasites causing sleeping sickness. APOL1 uptake into trypanosomes is favoured by its association with the haptoglobin-related protein-haemoglobin complex, which binds to the parasite surface receptor for haptoglobin-haemoglobin. As haptoglobin-haemoglobin can saturate the receptor, APOL1 uptake is increased in haptoglobin-poor (hypohaptoglobinaemic) serum (HyHS).

Resistance to normal human serum reveals Trypanosoma lewisi as an underestimated human pathogen.

Human-infectious trypanosomes such as Trypanosoma cruzi, T. brucei rhodesiense, and T. b.