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Due to its harmful, pro\u2010inflammatory potential, complement is controlled by several soluble and membrane\u2010bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. In this review, the current state of knowledge of the physiological functions of four complement regulators will be described: cartilage oligomeric matrix protein (<jats:styled-content style=\"fixed-case\">COMP<\/jats:styled-content>), <jats:styled-content style=\"fixed-case\">CUB<\/jats:styled-content> and sushi multiple domains 1 (<jats:styled-content style=\"fixed-case\">CSMD<\/jats:styled-content>1), sushi domain\u2010containing protein 4 (<jats:styled-content style=\"fixed-case\">SUSD<\/jats:styled-content>4) and <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>59. Complement activation is involved in both the development of and defence against cancer. <jats:styled-content style=\"fixed-case\">COMP<\/jats:styled-content> expression is pro\u2010oncogenic, whereas <jats:styled-content style=\"fixed-case\">CSMD<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">SUSD<\/jats:styled-content>4 act as tumour suppressors. These effects may be related in part to the complex influence of complement on cancer but also depend on unrelated functions such as the protection of cells from endoplasmic reticulum stress conveyed by intracellular <jats:styled-content style=\"fixed-case\">COMP<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>59 is the main inhibitor of the membrane attack complex, and its deficiency leads to complement attack on erythrocytes and severe haemolytic anaemia, which is now amenable to treatment with an inhibitor of C5 cleavage. Unexpectedly, the intracellular pool of <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>59 is crucial for insulin secretion from pancreatic \u03b2\u2010cells. This finding is one of several relating to the intracellular functions of complement proteins, which until recently were only considered to be present in the extracellular space. Understanding the alternative functions of complement inhibitors may unravel unexpected links between complement and other physiological systems, but is also important for better design of therapeutic complement inhibition.<\/jats:p>","DOI":"10.1111\/joim.12606","type":"journal-article","created":{"date-parts":[[2017,3,27]],"date-time":"2017-03-27T03:56:52Z","timestamp":1490587012000},"page":"116-128","source":"Crossref","is-referenced-by-count":73,"title":["The role of complement inhibitors beyond controlling inflammation"],"prefix":"10.1111","volume":"282","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1348-1734","authenticated-orcid":false,"given":"A. 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