DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis

Abstract

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations disrupting nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts expression of POLA1, the gene encoding the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency results in increased type I interferon production. This enzyme is necessary for RNA:DNA primer synthesis during DNA replication and strikingly, POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Altogether, this work identified POLA1 as a critical regulator of the type I interferon response.

Exome and genome sequencing for inborn errors of immunity

“…The genetic dissection of PIDs identified by NGS has also demonstrated new functions for known proteins. For instance, the catalytic subunit of polymerase alpha plays a crucial role in the synthesis of cytoplasmic RNA-DNA hybrids which avoid excessive type I interferon responses to other nucleic acids (77). Likewise ISG15, an anti-IFN-γ-inducing molecule was shown to be a strong negative regulator of IFN-α/β immunity through USP18 (78–80).…”

“…RNA genes are typically less well covered by WES than by WGS (11). In addition, WGS has resulted in the elucidation of the gene defect underlying X-linked reticulate pigmentary disorder after two decades of research had failed to identify the causative gene, the reason being that the mutation was located deeply into an intron (77). We can only speculate on the maximal proportion of disease-causing mutations not located in the exome – this may range from 5 up to 50%, depending on the PID category (81, 82).…”

Monogenic autoinflammatory disorders: beyond the periodic fever

“…117 The genetic causes of Aicardi-Goutières syndrome determined to date involve the processing or sensing of cytoplasmic nucleic acid. 124 Although not a key manifestation, intracranial calcifications are also seen in some patients with SAVI and systemic lupus erythematosus, 125,126 suggesting that this feature may be linked to interferon upregulation. Likewise, USP18 deficiency is also associated with intracranial calcification as well as microcephaly, cerebral haemorrhage and hepatosplenomegaly.…”

Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

“…While the clinical spectrum of the type I interferonopathies is highly variable and broad, neurological and cutaneous manifestations represent the most salient findings [7,8]. In addition, signs of immunodeficiency with recurrent infections can be observed in certain disease entities [9][10][11]. Although the implicated genes exert diverse biological functions, the associated disease pathways converge to a common route which is inappropriate overproduction of type I IFN (Table 1) [8].…”

“…1). Deficiency in the nucleases TREX1 or RNase H2, a lack of the triphosphohydrolase activity of SAMHD1 or loss of the DNA polymerase α results in abnormal accumulation of nucleic acids emanating from DNA repair/replication or the life cycle of retroelements causing a spectrum of phenotypes including Aicardi-Goutières syndrome (AGS), retinal vasculopathy with cerebral leukodystrophy (RVCL), familial chilblain lupus (CHBL), or X-linked reticulate pigmentary disorder (XLPDR) [11][12][13][14][15][16][17]. Similarly, a lack of the RNA-specific deaminase ADAR or loss of the RNase activity of SAMHD1 alters the chemical properties of RNA or causes accumulation of RNA species which triggers type I IFN activation [18,19].…”