Complement factor H family proteins in their non-canonical role as modulators of cellular functions

Abstract

Complement factor H is a major regulator of the alternative pathway of the complement system. The factor H-related proteins are less characterized, but recent data indicate that they rather promote complement activation. These proteins have some common ligands with factor H and have both overlapping and distinct functions depending on domain composition and the degree of conservation of amino acid sequence. Factor H and some of the factor H-related proteins also appear in a non-canonical function that is beyond their role in the modulation of complement activation. This review covers our current understanding on this emerging role of factor H family proteins in modulating the activation and function of various cells by binding to receptors or receptor ligands.

Lipopolysaccharide-stimulated, NF-kB-, miRNA-146a- and miRNA-155-mediated molecular-genetic communication between the human gastrointestinal tract microbiome and the brain

“…Briefly, a small family of NF-kB (p50/p65 complex) induced pro-inflammatory microRNAs (miRNAs), including miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155, ultimately bind with the 3'-UTR of several target messenger RNAs (mRNAs) and thereby decrease their expression. Down-regulated mRNAs include those encoding the SH3-proline-rich multi-domain-scaffolding protein of the postsynaptic density (SHANK3), the triggering receptor expressed in myeloid/microglial cells (TREM2) and complement factor-H (CFH); similar deficiencies in these 3 proteins are also observed in sporadic AD brain [20,27,28,36,89,90]. The critical importance of a down-regulated CFH mRNA and protein, and hence the observed deficits in CFH expression and abundance in AD in this scheme due to up-regulated pro-inflammatory miRNA-146a and miRNA-155 is particularly significant.…”

“…One energetically favorable miRNA-146a and/or miRNA-155 mRNA target, both confirmed by bioinformatics and miRNA-mRNA-3'-UTR binding luciferase-reporter assay, is the 3'-untranslated region (3'-UTR) of complement factor H (CFH) mRNA resulting in, respectively, the down-regulation of CFH expression [26,27,48,87]. A down-regulated CFH is associated with the disruption of innate-immune signaling that supports inflammatory neurodegeneration and amyloidogenesis [17,34,36,45,55,75,[89][90][91]. Although CFH is easily detected in the brain parenchyma and neuronal cytoplasm it is also highly abundant in the blood serum of the human systemic circulation, as may be some other pathogenic blood-cell-based biomarkers that may include specific kinase mutations and other polymorphisms [17,45,55,68,91; see also https://www.sigmaaldrich.com/catalog/product/sigma/c5813?lang=en&region=US; ENSG000 00000971-CFH/ tissue; last accessed 4 July 2019].…”

“…The critical importance of a down-regulated CFH mRNA and protein, and hence the observed deficits in CFH expression and abundance in AD in this scheme due to up-regulated pro-inflammatory miRNA-146a and miRNA-155 is particularly significant. CFH down-regulation is further discussed below due to its critical role in the regulation of the innate-immune response and the onset and propagation of neuro-degeneration and inflammatory signaling [16,36,43,50,52,53,55] (Fig. 1).…”

“…Complement factor H (CFH; GC01P196621), encoded from the regulator of complement activation gene cluster at human chromosome 1q31.3, is a large, structurally versatile and critical 155 kDa soluble glycoprotein moderately expressed in the human neocortex and retina, and highly expressed in the gall bladder and the liver where the mature plasma form of CFH passes into the systemic circulation [36,50,52,53]; , when stressed, release a broad spectrum of highly pro-inflammatory and potentially pathogenic molecules into the surrounding medium; these molecules comprise five major classes of secreted neurotoxins that include lipooligosaccharide (LOS) and lipopolysaccharide (LPS), exotoxins (such as fragilysin), endotoxins, bacterial amyloids, and small non-coding RNAs (sncRNAs) [7,[12][13][14][24][25][26][27]87]. Normally, a highly dynamic GI-tract barrier keeps bacteria and their neurotoxic exudates compartmentalized within the GI-tract; however, with aging and disease these barriers become 'leaky' and the same neurotoxins can easily transit GI-tract barriers to enter the systemic circulation.…”

“…Normal human plasma concentrations of CFH range between ~200 and 300 ug/ml, the highest of any plasma complement protein, and as such represents the major human complement regulator in human blood, brain and retina [17,55; unpublished]. CFH is composed of ~20 tandem ~60 amino-acid 'complement control protein' modules each connected by 3-8 amino acid linkers whose principal function is to regulate the alternative pathway of complement system activation, a central component of the innate-immune system's natural defense against pathogens and microbial infection [27,28,36,52,[88][89][90]. As the major immune regulator of the innate-immune system, CFH recognizes pathogen-and damage-associated molecular patterns (DAMPs) and initiates an immune response in coordination with innate and adaptive immunity [36,52,53,[88][89][90].…”