Novel potential inhibitors of complement system and their roles in complement regulation and beyond

The complement system resembles a double-edged sword since its activation can either benefit or harm the host. Thus, regulation of this system is of utmost importance and performed by several circulating and membrane-bound complement inhibitors. The pool of well-established regulators has recently been enriched with proteins that either share structural homology to known complement inhibitors such as Sushi domain-containing (SUSD) protein family and Human CUB and Sushi multiple domains (CSMD) families or extracellular matrix (ECM) macromolecules that interact with and modulate complement activity. In this review, we summarize the current knowledge about newly discovered complement inhibitors and discuss their implications in complement regulation, as well as in processes beyond complement regulation such cancer development. Understanding the behavior of these proteins will introduce new mechanisms of complement regulation and may provide new avenues in the development of novel therapies.