Inflammation-linked apolipoprotein-L activities: immunity control, mitochondrial repair, pathogen resistance, and disease induction

Pays, Etienne*

Laboratory of Molecular Parasitology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Belgium

*Correspondence to: Etienne Pays, PhD, etienne.pays@gmail.com.

Abstract

This review details the structure and functions of three members of the human apolipoprotein (APOL) family, namely, APOL1, APOL2, and APOL3. APOL1 and APOL3 are selectively induced by type I interferon-mediated inflammation. APOL1 is associated with factors that drive Golgi-derived vesicles to mitochondrion‒endoplasmic reticulum contact sites. This trafficking is induced by type I interferon to initiate mitophagy or apoptosis, which are crucial mitochondrial repair mechanisms in response to inflammatory damage. APOL3 is in a trimeric complex that controls the synthesis of the membrane phospholipid phosphatidylinositol-4-phosphate at the Golgi. When delocalized with APOL1 at mitochondrion‒endoplasmic reticulum contact sites following inflammation, PI(4)P kinase-B activity induces mitochondrial membrane fission for mitophagosome formation, and APOL3 promotes membrane fusion between mitophagosomes and endolysosomes to complete mitophagy. Thus, APOL1 and APOL3 control inflammation-linked vesicular trafficking and mitochondrial membrane dynamics, respectively. Chronic kidney disease can result from either the expression of APOL1 C-terminal variants or APOL3 deletion. Depending on inflammation, APOL1-mediated kidney disease, termed APOL1 nephropathy, is associated with two levels of podocyte cytopathology (hit 1 and hit 2). Both pathology levels involve actomyosin modifications, mitochondrial dysfunctions, and stress signaling, but inflammation-linked hit 2 is characterized by increased severity. Different C-terminal APOL1 variants, such as the G1 or G2 variants that allow humans to resist infection by pathogenic African trypanosomes, exhibit increased hydrophobicity, likely due to structural unfolding. These variants display increased interaction with APOL3, inhibiting APOL3 functions and mimicking experimental or natural APOL3 deletion. Thus, hit 1 may result from the inactivation of APOL3 membrane remodeling activities. Hit 2 is due to increased podocyte surface cation fluxes, which induce cytotoxicity through stress signaling. Two models can account for hit 2: either secreted G1 or G2 generates cation channels at the podocyte surface, or these variants activate existing cholesterol-dependent cation channels. In this review, I argue in favor of the second model. The closest APOL1 homolog, APOL2, can be considered another C-terminal variant. Accordingly, increased APOL2 expression induced by transforming growth factor-β1 could cause liver fibrosis and modulate gut mucosal immunity through exocytotic trafficking of vesicles carrying inactivated APOL3. APOL2 may also be involved in antigen cross-presentation and the apoptosis of dendritic cells via membrane permeabilization resulting from altered membrane fission-fusion by APOL3. In conclusion, through their basic functions in membrane remodeling, APOLs 1–3 are involved in various processes linked to cellular activation by either type I interferon or transforming growth factor-β1. In addition to APOL1-mediated kidney disease and liver fibrosis, other APOL-related diseases await discovery.

涉及炎症驱动的线粒体修复和载脂蛋白L1肾病的载脂蛋白-L：叙述性综述

摘要

由载脂蛋白L控制的有丝分裂或细胞凋亡是线粒体在炎症损伤时的重要修复机制。在人类载脂蛋白L家族的不同成员中，载脂蛋白L1 和载脂蛋白L3 的特点是在 I 型干扰素诱导的炎症情况下，它们的特异性表达会增加。尽管这两种蛋白的序列高度相似，但它们在结构和功能上却存在重要差异。载脂蛋白L1 和 载脂蛋白L3 分别控制着与炎症有关的囊泡贩运和线粒体膜动力学。表达载脂蛋白L1 C 端变体（“风险变体”）或 载脂蛋白L3 缺失都可能导致慢性肾病。根据炎症的不同，这种疾病被称为载脂蛋白L1 肾病或载脂蛋白L1 介导的肾病，表现出两种程度的荚膜细胞病理学（命中 1 和命中 2）。这两种荚膜细胞功能障碍模式都涉及肌动蛋白修饰、线粒体功能障碍和应激信号转导，但与炎症相关的 “命中 2 ”的特点是严重性增加。不同的 C 端载脂蛋白L1 变体（如 G1 或 G2 变体）可使人类抵御致病性非洲锥虫的感染，它们表现出更强的疏水性，这可能是由于 C 端亮氨酸拉链螺旋体（LZ2）的序列分异引发了结构解折。这些变体与载脂蛋白L3 的相互作用增强，抑制了载脂蛋白L3 的功能，并模拟了实验性或天然 载脂蛋白L3 缺失（载脂蛋白L3 KO）。因此，基因突变 1 可能是 载脂蛋白L3 膜重塑活性失活的结果。至于命中 2，则是由于表面阳离子通量增加，通过应激信号诱发了细胞病理学。有两种模式可以解释命中 2：要么是分泌的 G1 或 G2 在荚膜细胞表面生成阳离子通道，要么是这些变体由于疏水性增加而激活了现有的胆固醇依赖性阳离子通道。这篇综述支持第二种模式，旨在总结涉及炎症驱动的线粒体修复和载脂蛋白L1 肾病的载脂蛋白L作用机制。