A complement factor H homolog, heparan sulfation, and syndecan maintain inversin compartment boundaries in C. elegans cilia

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Canonical disease models suggest that defective interactions between complement factor H (CFH) and cell surface heparan sulfate (HS) result in increased alternative complement pathway activity, cytolytic damage, and tissue inflammation in the retina. Although these factors are thought to contribute to increased disease risk, multiple studies indicate that noncanonical mechanisms that result from defective CFH and HS interaction may contribute to the progression of AMD as well. A total of 60 ciliated sensory neurons in the nematode Caenorhabditis elegans detect chemical, olfactory, mechanical, and thermal cues in the environment. Here, we find that a C. elegans CFH homolog localizes on CEP mechanosensory neuron cilia where it has noncanonical roles in maintaining inversin/NPHP-2 within its namesake proximal compartment and preventing inversin/NPHP-2 accumulation in distal cilia compartments in aging adults. CFH localization and maintenance of inversin/NPHP-2 compartment integrity depend on the HS 3-O sulfotransferase HST-3.1 and the transmembrane proteoglycan syndecan/SDN-1. Defective inversin/NPHP-2 localization in mouse and human photoreceptors with CFH mutations indicates that these functions and interactions may be conserved in vertebrate sensory neurons, suggesting that previously unappreciated defects in cilia structure may contribute to the progressive photoreceptor dysfunction associated with CFH loss-of-function mutations in some AMD patients.

The Role of Sulfation in Nematode Development and Phenotypic Plasticity

“…Finally, HS modifications have also been shown to regulate cilia structure in C. elegans ( Acker et al, 2021 ). The cilia protrusions are organized in highly compartmentalized microtubule-based domains and disruption of their composition and structure results in ciliopathies ( Reiter and Leroux, 2017 ).…”

“…HST-3.1 is proposed to modify the HS chain of proteoglycans that recruit CFH in the mechanosensory neurons. In the absence of this modification, CFH is not properly localized in the cilia and the animals show defects in mechanosensory neuron function ( Acker et al, 2021 ). The role of HS modifications in cilia structure is another example of how studies in nematodes increase our knowledge on disease associated processes, since CFH is a major risk factor for age-related macular degeneration and blindness in humans ( Edwards et al, 2005 ; Hageman et al, 2005 ; Haines et al, 2005 ; Klein et al, 2005 ; Zareparsi et al, 2005 ).…”