![Figure 1. Type I interferon signaling and type I interferonopathies as currently assigned. Diseases considered as monogenic interferonopathies are represented by blue boxes. This schema alludes to at least seven possible cellular mechanisms resulting in sustained activation of interferon signaling caused by the following: (1) loss-of-function mutations leading to increased cytosolic DNA (TREX1 [Stetson et al., 2008] and SAMHD1 [Behrendt et al., 2013; Rehwinkel et al., 2013]) or RNA/DNA hybrid (RNASEH2A, RNASEH2B and RNASEH2C, POLA1) sensing (Hiller et al., 2012; Mackenzie et al., 2016; Starokadomskyy et al., 2016); (2) loss-of-function mutations leading to a defect in RNA editing and abnormal sensing of self–nucleic acid RNA species in the cytosol (ADAR1 [Liddicoat et al., 2015; Pestal et al., 2015]); (3) gain-of-function mutations leading to constitutive activation of cytosolic interferon signaling pathways/increased sensitivity to cytosolic nucleic acid ligands (MDA5 [Rice et al., 2014], RIG-I [Jang et al., 2015], and STING [Liu et al., 2014]); (4) loss-of-function mutations leading to aberrant RNA signaling via MAVS caused by a disturbance of the unfolded protein response (SKIV2L [Eckard et al., 2014]); (5) loss-of-function mutations in molecules responsible for limiting interferon receptor (IFNAR1/2) signaling leading to uncontrolled ISG production (USP18 [Meuwissen et al., 2016] and ISG15 [Zhang et al., 2015]); (6) proteasomal dysfunction leading to increased interferon signaling through an unknown mechanism (PSMA3, PSMB4, and PSMB8 [Brehm et al., 2015]; we do not include the so-far single-published mutations in PSMB9 and POMP); and (7) loss-of-function mutations in TRAP/ACP5 (Briggs et al., 2011; Lausch et al., 2011) and C1q (Lood et al., 2009; Santer et al., 2010) where we consider the mechanisms leading to type I interferon signaling are yet to be fully clarified (we do not include mutations in other molecules of the complement pathway as a clear demonstration of enhanced interferon signaling has not been established).](https://cdn.rupress.org/rup/content_public/journal/jem/213/12/10.1084_jem.20161596/6/jem_20161596_fig1.jpeg?Expires=1767755440&Signature=25L3uOjbWIyMv9kUfuXiGarO1WLL0ENQ52e6k-hEhQJA7Ia~HlZF0ZWtmd5vubBTmRhXifHUN227YsojJvYY9RdhLUL1K~iDrMqlZLBIzTaJ3iSitqeh6GMH1D-g78oFYwtQ~5S~boxafk4C9XHqkumJyJn2kpstW8RFZlP4jsG7Cd~2s~YVQDpjuvbvNP~WHUpaRAsiIHccieBHn88b2EvJDMweaJ2LYTBcqcrrSCFFzTLfqzzslgT9pQZsud8MBF~uQnZxPzS4DVy9iUEvmQE9Zaf4zxhKoUoNPGE3TWZkeOu-3q4eaIsgA5n7kec-Qxwc8qR5WRiEnyJXw82Y~Q__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Type I interferon signaling and type I interferonopathies as currently assigned. Diseases considered as monogenic interferonopathies are represented by blue boxes. This schema alludes to at least seven possible cellular mechanisms resulting in sustained activation of interferon signaling caused by the following: (1) loss-of-function mutations leading to increased cytosolic DNA (TREX1 [Stetson et al., 2008] and SAMHD1 [Behrendt et al., 2013; Rehwinkel et al., 2013]) or RNA/DNA hybrid (RNASEH2A, RNASEH2B and RNASEH2C, POLA1) sensing (Hiller et al., 2012; Mackenzie et al., 2016; Starokadomskyy et al., 2016); (2) loss-of-function mutations leading to a defect in RNA editing and abnormal sensing of self–nucleic acid RNA species in the cytosol (ADAR1 [Liddicoat et al., 2015; Pestal et al., 2015]); (3) gain-of-function mutations leading to constitutive activation of cytosolic interferon signaling pathways/increased sensitivity to cytosolic nucleic acid ligands (MDA5 [Rice et al., 2014], RIG-I [Jang et al., 2015], and STING [Liu et al., 2014]); (4) loss-of-function mutations leading to aberrant RNA signaling via MAVS caused by a disturbance of the unfolded protein response (SKIV2L [Eckard et al., 2014]); (5) loss-of-function mutations in molecules responsible for limiting interferon receptor (IFNAR1/2) signaling leading to uncontrolled ISG production (USP18 [Meuwissen et al., 2016] and ISG15 [Zhang et al., 2015]); (6) proteasomal dysfunction leading to increased interferon signaling through an unknown mechanism (PSMA3, PSMB4, and PSMB8 [Brehm et al., 2015]; we do not include the so-far single-published mutations in PSMB9 and POMP); and (7) loss-of-function mutations in TRAP/ACP5 (Briggs et al., 2011; Lausch et al., 2011) and C1q (Lood et al., 2009; Santer et al., 2010) where we consider the mechanisms leading to type I interferon signaling are yet to be fully clarified (we do not include mutations in other molecules of the complement pathway as a clear demonstration of enhanced interferon signaling has not been established).
