Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

Meuwissen, Marije; Schot, Rachel; Buta, Sofija; Oudesluijs, Grétel; Tinschert, Sigrid; Speer, Scott D.; Zhi, Li; Unen, Leontine van; Heijsman, Daphne; Goldmann, Tobias; Lequin, Maarten H.; Kros, Johan M.; Stam, Wendy; Hermann, Michael; Willemsen, Rob; Brouwer, Rutger W. W.; IJcken, Wilfred F. J. van; Martín-Fernández, Marta; Coo, I.F.M. de; Dudink, Jeroen; Vries, Femke A.T. de; Avella, Aida Bertoli; Prinz, Marco; Crow, Yanick J.; Verheijen, Frans W.; Pellegrini, Sandra; Bogunovic, Dusan; Mancini, Grazia M.S.

doi:10.1084/jem.20151529

Cited by 233 publications

(216 citation statements)

References 31 publications

Supporting

Mentioning

199

Contrasting

Order By: Relevance

“…Therefore, dysregulation of IFN signaling results in a loss of microglial homeostasis in the adult CNS (Figure 2). Notably, the recent identification of Usp18-deficient patients with severe brain abnormalities underscores the essential role of USP18 for normal CNS homeostasis (113).…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E Nmentioning

confidence: 99%

Microglia in steady state

Kierdorf¹,

Prinz²

2017

Journal of Clinical Investigation

Self Cite

227

179

View full text Add to dashboard Cite

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E Nmentioning

confidence: 99%

Microglia in steady state

Kierdorf¹,

Prinz²

2017

Journal of Clinical Investigation

Self Cite

227

179

View full text Add to dashboard Cite

“…Consequences of TORCH syndrome include microcephaly, white matter disease, cerebral atrophy, and calcifications in the CNS. Pseudo-TORCH syndrome (PTS) refers to infants born with a clinical phenotype that matches TORCH, but for which there is a non-infectious cause [99]. The genetic cause in most PTS cases is unknown.…”

Section: Dysregulation Of Type I Ifn Signaling Leads To White Mattermentioning

confidence: 99%

“…This group of disorders includes cases of ISG15 deficiency in humans, which exhibit abnormally strong type I IFN responses and elevated levels of type I IFNs, intracranial calcification, a predisposition towards epileptic seizures, and low levels of USP18 [100]. In another recent study, Meuwissen et al [99] made clinical observations of two unrelated families affected with PTS demonstrating that patients with a genetic mutation in usp18 displayed a neuropathological and neuroimmune phenotype matching mouse models of usp18 deficiency, including a strong induction of the innate immune system as evidenced by robust induction of activated astrocytes and microglia in patient brains, and high constitutive activation of phosphorylated STAT1 [99]. Fibroblasts derived from patient tissues also demonstrated high levels of ISG transcripts as a consequence of unrestrained IFN signaling [99].…”

Section: Dysregulation Of Type I Ifn Signaling Leads To White Mattermentioning

confidence: 99%

Microglial Interferon Signaling and White Matter

2017

View full text Add to dashboard Cite

Microglia, the resident immune cells of the CNS, are primary regulators of the neuroimmune response to injury. Type I interferons (IFNs), including the IFNαs and IFNβ, are key cytokines in the innate immune system. Their activity is implicated in the regulation of microglial function both during development and in response to neuroinflammation, ischemia, and neurodegeneration. Data from numerous studies in multiple sclerosis (MS) and stroke suggest that type I IFNs can modulate the microglial phenotype, influence the overall neuroimmune milieu, regulate phagocytosis, and affect blood–brain barrier integrity. All of these IFN-induced effects result in numerous downstream consequences on white matter pathology and microglial reactivity. Dysregulation of IFN signaling in mouse models with genetic deficiency in ubiquitin specific protease 18 (USP18) leads to a severe neurological phenotype and neuropathological changes that include white matter microgliosis and pro-inflammatory gene expression in dystrophic microglia. A class of genetic disorders in humans, referred to as pseudo-TORCH syndrome (PTS) for the clinical resemblance to infection-induced TORCH syndrome, also show dysregulation of IFN signaling, which leads to severe neurological developmental disease. In these disorders, the excessive activation of IFN signaling during CNS development results in a destructive interferonopathy with similar induction of microglial dysfunction as seen in USP18 deficient mice. Other recent studies implicate “microgliopathies” more broadly in neurological disorders including Alzheimer’s disease (AD) and MS, suggesting that microglia are a potential therapeutic target for disease prevention and/or treatment, with interferon signaling playing a key role in regulating the microglial phenotype.

show abstract

“…Interestingly, in human cells, ISG15 directly regulates USP18 stability 24 . Furthermore, critical functions of USP18 in IFN mediated immune responses are demonstrated in mouse and human models 25–32 suggesting the broad impact of USP18 in immune responses and therapeutic potential of modulating USP18 inhibitory effects.…”

Section: Introductionmentioning

confidence: 99%

STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling

Arimoto

Löchte

Stoner

et al. 2017

Nat Struct Mol Biol

Self Cite

157

164

View full text Add to dashboard Cite

Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn interferes with medical interventions. The JAK-STAT signaling pathway transmits the IFN extracellular signal to the nucleus for alterations of gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized crucial component of the USP18-mediated negative feedback control in both, human and murine cells. We found that STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2 binding site. This mechanistic coupling of effector and negative feedback functions of STAT2 provides novel strategies in treatment of IFN signaling related human diseases.

show abstract

Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

Abstract: Meuwissen and collaborators define a novel genetic cause of pseudo-TORCH syndrome, which resembles the sequelae of congenital infection and represents a novel type I interferonopathy.

Cited by 233 publications

References 31 publications

Microglia in steady state

Microglia in steady state

Microglial Interferon Signaling and White Matter

STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling

Contact Info

Product

Resources

About