Immune Diseases Associated with TREX1 and STING Dysfunction

Abstract

The innate immune system is the first line of defense against invading pathogens. One important feature of innate immune recognition is self versus nonself discrimination. The selectivity for microbial ligands is achieved through substrate motif specificity, spatial compartmentalization, and functions of negative regulators. Loss-of-function mutations in negative regulators or gain-of-function mutations in drivers of innate immune signaling have been associated with autoimmune diseases such as lupus, rheumatoid arthritis, inflammatory vasculopathy, and a variety of interferonopathies. This review will focus on TREX1 and STING, which are opposing regulators of the cytosolic DNA-sensing pathway. Tremendous effort over the past decade among academic and clinical research groups has elucidated molecular mechanisms underlying immune diseases associated with TREX1 and STING dysfunction. We have also witnessed rapid therapeutic translation of the molecular findings. Several targeted treatment options or druggable candidates are now available for these once incurable diseases. With great enthusiasm from both academia and industry partners, we look forward to seeing the remaining scientific questions answered and, more importantly, the affected patients benefited from these discoveries.

Keywords: Aicardi–Goutières syndrome; STING; STING-associated vasculopathy with onset in infancy; TREX1; cytosolic DNA sensing; retinal vasculopathy with cerebral leukodystrophy.

FIG. 1.

An overall model of innate immune signaling involved in TREX1- and STING-associated immune diseases. Yellow asterisks indicate location of disease-associated mutation. AGS, Aicardi–Goutières syndrome; FCL, familial chilblain lupus; RVCL, retinal vasculopathy with cerebral leukodystrophy; SAVI, STING-associated vasculopathy with onset in infancy; SLE, systemic lupus erythematosus. Color images available online at www.liebertpub.com/jir

FIG. 2.

TREX1 mutations and associated immune diseases. (A) A diagram of TREX1 protein and mutations associated various autoimmune and inflammatory diseases. (B) A diagram of 2 distinct functions of TREX1. TM, transmembrane domain. Color images available online at www.liebertpub.com/jir

FIG. 3.

STING mutations and associated immune diseases. TM, transmembrane domain. CDN, cyclic dinucleotide; TBD, TBK1 binding domain. Color images available online at www.liebertpub.com/jir