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Cells
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Evolution, Structure, and Functions of Apolipoproteins L
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Evolution, Structure, and Functions of Apolipoproteins L

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 30 September 2025 | Viewed by 3075

Special Issue Editor

Dr. Etienne Pays

E-Mail Website
Guest Editor
Laboratory of Molecular Parasitology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, 6041 Gosselies, Belgium
Interests: molecular parasitology; cellular biology

Special Issue Information

Dear Colleagues,

Apolipoproteins L are mammalian hydrophobic proteins encoded in multigene families exhibiting a dynamic evolution. The first identified member, APOL1, is associated with cholesterol-rich high-density lipoprotein particles, and conveys human resistance to infection by the bloodstream African parasite Trypanosoma brucei. Accordingly, the expression of this protein is strongly increased upon inflammation linked to pathogen infection. Such also occurs for APOL3, which confers resistance to intracellular bacteria. Moreover, both APOL1 and APOL3 are involved in the control of viral replication. Regarding the other human family members, the information is scarce except that APOL4 is a prognostic biomarker for glioma, and APOL6 is involved in the control of lipid droplets’ size. Finally, the recent natural APOL1 evolution linked to the continuous arms race between humans and African trypanosomes has revealed that C-terminal APOL1 sequence alteration induces chronic kidney disease due to podocyte dysfunctions. Such heterogeneous phenotype pattern is indicative of a basic general function of APOLs for the control of cell biology. Accordingly, recent observations suggest that APOLs control the dynamics of intracellular membranes (traffic, fission, and fusion), which are crucial for membrane remodeling, particularly upon pathogen infection. Relevant processes include (neuro)secretion, autophagy, mitophagy, apoptosis, and the building of viral replication platforms. Through its linkage with the control of actomyosin activity, this topic also pertains to the control of cellular architecture and mobility, and extends to processes involved in metastasis.

Dr. Etienne Pays
Guest Editor

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Keywords

  • APOL1 nephropathy
  • APOL1 risk variants
  • membrane traffic
  • membrane fission
  • membrane fusion
  • membrane dynamics
  • autophagy
  • mitophagy
  • viral replication
  • lipid droplets
  • pathogen resistance
  • inflammation

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Published Papers (3 papers)

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Research

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30 pages, 3854 KiB  
Article
Apolipoprotein L1 (APOL1): Consideration of Molecular Evolution, Interaction with APOL3, and Impact of Splice Isoforms Advances Understanding of Cellular and Molecular Mechanisms of Cell Injury
by Razi Khalaila and Karl Skorecki
Cells 2025, 14(13), 1011; https://doi.org/10.3390/cells14131011 - 2 Jul 2025
Viewed by 299
Abstract
The Apolipoprotein L1 (APOL1) innate immunity gene product represents the sole member of the APOL gene family in humans capable of secretion into circulation, thereby mediating the trypanolysis of T. brucei brucei. Gain-of-function variants of the APOL1 gene originated and spread among [...] Read more.
The Apolipoprotein L1 (APOL1) innate immunity gene product represents the sole member of the APOL gene family in humans capable of secretion into circulation, thereby mediating the trypanolysis of T. brucei brucei. Gain-of-function variants of the APOL1 gene originated and spread among human population groups to extend APOL1’s protective capacity to include also serum-resistant subspecies, such as T. brucei gambiense (S342G known as APOL1-G1) and T. brucei rhodesiense (N388_Y389del known as APOL1-G2). The biochemical pathways underlying the lytic activity of these evolutionary favored mutations against bloodstream trypanosomes have been elucidated with remarkable precision. However, the intricate molecular mechanisms by which such variants confer an increased susceptibility to renal cellular injury and consequent kidney disease remain incompletely defined. In the absence of a consistent mechanistic explanation for differential kidney injury, we propose pursuing three interrelated avenues of investigation informed by prior epidemiological and mechanistic evidence linking them to APOL1’s cytotoxicity: (1) Molecular evolution of APOL1 haplotypes in human populations, (2) APOL1 splicing and consequent splice isoforms, (3) Interaction of APOL1 with other APOL gene family members, prioritizing APOL3. In the current study, we use reanalysis of population genetics datasets to resolve the haplotype contexts of all protein-altering APOL1 variants, uncovering previously unrecognized variant–haplotype couplings. We further characterize distinct cellular physiological properties among APOL1 splice isoforms, stressing the importance of isoform vB and what can be learned from isoform vC. Finally, a native interaction, and its interface, between APOL1 and APOL3 is reported, and shown to be differentially modulated by G1 and G2. We contend that continuing studies integrating these three interrelated domains will substantially advance mechanistic insights into APOL1 variant-driven renal injury, and leverage the findings to provide a more cohesive framework to guide future research. Full article
(This article belongs to the Special Issue Evolution, Structure, and Functions of Apolipoproteins L)
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Review

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24 pages, 3513 KiB  
Review
A Cell Biologist’s View on APOL1: What We Know and What We Still Need to Address
by Verena Höffken, Daniela Anne Braun, Hermann Pavenstädt and Thomas Weide
Cells 2025, 14(13), 960; https://doi.org/10.3390/cells14130960 - 24 Jun 2025
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Abstract
APOL1 is the most recent member of the APOL gene family and is expressed exclusively in humans and a few higher primates. More than twenty years ago, it was discovered that APOL1 protects humans from infections by trypanosome subspecies that cause African sleeping [...] Read more.
APOL1 is the most recent member of the APOL gene family and is expressed exclusively in humans and a few higher primates. More than twenty years ago, it was discovered that APOL1 protects humans from infections by trypanosome subspecies that cause African sleeping sickness. Interestingly, by a co-evolutionary process between parasite and host, two APOL1 variants emerged, which, in addition to their trypanotoxic effects, are simultaneously associated with a significantly increased risk for various different kidney diseases, which are now summarized as APOL1-mediated kidney diseases (AMKDs). The aim of this review is to highlight and formulate key aspects of APOL1’s cell biologic features, including questions and unaddressed aspects. This perspective may contribute to a deeper understanding of APOL1-associated cytotoxicity as well as AMKDs. Full article
(This article belongs to the Special Issue Evolution, Structure, and Functions of Apolipoproteins L)
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22 pages, 2994 KiB  
Review
Apolipoprotein-L Functions in Membrane Remodeling
by Etienne Pays
Cells 2024, 13(24), 2115; https://doi.org/10.3390/cells13242115 - 20 Dec 2024
Cited by 3 | Viewed by 1937
Abstract
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 [...] Read more.
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). These vesicles deliver APOL3 together with phosphatidylinositol-4-kinase-B (PI4KB) and activated Stimulator of Interferon Genes (STING) to mitochondrion–endoplasmic reticulum (ER) contact sites (MERCSs) for the induction and completion of mitophagy and apoptosis. Through direct interactions with PI4KB and PI4KB activity controllers (Neuronal Calcium Sensor-1, or NCS1, Calneuron-1, or CALN1, and ADP-Ribosylation Factor-1, or ARF1), APOL3 controls PI(4)P synthesis. PI(4)P is required for different processes linked to infection-induced inflammation: (i) STING activation at the Golgi and subsequent lysosomal degradation for inflammation termination; (ii) mitochondrion fission at MERCSs for induction of mitophagy and apoptosis; and (iii) phagolysosome formation for antigen processing. In addition, APOL3 governs mitophagosome fusion with endolysosomes for mitophagy completion, and the APOL3-like murine APOL7C is involved in phagosome permeabilization linked to antigen cross-presentation in dendritic cells. Similarly, APOL3 can induce the fusion of intracellular bacterial membranes, and a role in membrane fusion can also be proposed for endothelial APOLd1 and adipocyte mAPOL6, which promote angiogenesis and adipogenesis, respectively, under inflammatory conditions. Thus, different APOL isoforms play distinct roles in membrane remodeling associated with inflammation. Full article
(This article belongs to the Special Issue Evolution, Structure, and Functions of Apolipoproteins L)
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