Abstract
The Sez6 family consists of Sez6, Sez6L, and Sez6L2. Its members are expressed throughout the brain and have been shown to influence synapse numbers and dendritic morphology. They are also linked to various neurological and psychiatric disorders. All Sez6 family members contain 2-3 CUB domains and 5 complement control protein (CCP) domains, suggesting that they may be involved in complement regulation. We show that Sez6 family members inhibit C3b/iC3b opsonization by the classical and alternative pathways with varying degrees of efficacy. For the classical pathway, Sez6 is a strong inhibitor, Sez6L2 is a moderate inhibitor, and Sez6L is a weak inhibitor. For the alternative pathway, the complement inhibitory activity of Sez6, Sez6L, and Sez6L2 all equaled or exceeded the activity of the known complement regulator MCP. Using Sez6L2 as the representative family member, we show that it specifically accelerates the dissociation of C3 convertases. Sez6L2 also functions as a cofactor for Factor I to facilitate the cleavage of C3b; however, Sez6L2 has no cofactor activity toward C4b. In summary, the Sez6 family are novel complement regulators that inhibit C3 convertases and promote C3b degradation.
Highlights
The Sez6 family, consisting of Sez6, Sez6L, and Sez6L2, is notable because its members have been identified as potential susceptibility genes for multiple neurodevelopmental and psychiatric disorders including: autism, schizophrenia, intellectual disability, epilepsy, and bipolar disorder [1,2,3,4,5,6,7,8,9]
Diffuse Sez6L2 is found throughout the neuropil of the stratum radiatum and stratum oriens where a subset of Sez6L2 puncta co-localize with synapses (Figures 1B, C)
We have shown that Sez6, Sez6L, and Sez6L2 are all novel complement regulators that inhibit C3b/iC3b opsonization by the classical and alternative pathways
Summary
The Sez family, consisting of Sez, Sez6L, and Sez6L2, is notable because its members have been identified as potential susceptibility genes for multiple neurodevelopmental and psychiatric disorders including: autism, schizophrenia, intellectual disability, epilepsy, and bipolar disorder [1,2,3,4,5,6,7,8,9]. Sez family proteins are expressed by neurons throughout the brain during development and in adulthood. Some brain regions express multiple Sez family members, suggesting possible redundancy, while other regions have differential expression [11,12,13,14,15]. A few binding partners of the Sez family have been proposed [24,25,26,27,28], the molecular mechanisms and functions of Sez proteins are still unclear
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