Innate immune response in infections and autoimmune diseases
The Yan lab is primarily interested in the molecular mechanisms of innate immunity and how they impact infectious and autoimmune diseases. We all know that innate immune signaling pathways are essential for detecting pathogens, and mutations in key molecules of these pathways can also cause autoimmune diseases. We study both ends of the spectrum, with a strong focus on monogenic immune diseases that affect genes that also play important roles in infection
HIV evasion of innate immunity
One of the focuses in the Yan lab is to understand how HIV exploits host factors to evade innate immune detection. Viral nucleic acids introduced into cells or synthesized during infection trigger cytosolic sensors of innate immunity to produce antiviral cytokines, such as type I interferons (IFN). Some viruses evade immune sensing. Although HIV introduces genomic RNA and then generates a variety of DNA products in the cytosol through reverse transcription, HIV infection of T cells and macrophages does not trip these alarms. How HIV avoids activating innate immune sensors of foreign nucleic acids is an important area of interest. Few copies of HIV DNA integrate in a cell during infection, leaving behind some HIV DNA in the cytosol. Unintegrated HIV DNA is believed to be cleared by host enzymes. We found that the cytosolic exonuclease TREX1 suppressed interferon triggered by HIV (Yan et al 2010 Nature Immunology). In the absence of TREX1, HIV DNA is sensed by cytosolic DNA sensor cGAS and activates IFN response through the cGAS-cGAMP-STING pathway (Gao et al 2013 Science).
Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA and Lieberman J. The cytosolic exonuclease TREX1 inhibits the innate immune response to HIV-1. Nature Immunology 2010 Nov;11(11):1005-13. PMCID:PMC2958248
Yan N and Lieberman J. Gaining a Foothold: How HIV avoids innate immune recognition. Current Opinion in Immunology, 2011 Feb;23(1):21-8. Review. PMCID:PMC3042516
Yan N and Chen ZJ. Intrinsic antiviral immunity. Nature Immunology. 2012 Feb 16;13(3):214-22. Review. PMID: 22344284.
Yan N and Lieberman J. SAMHD1 does it again, in resting T cells. Nature Medicine, 2012 Nov; 18(11):1611-2. Review. PMID: 23135508.
Gao D, Wu JX, Wu YT, Du FH, Aroh C, Yan N, Sun LJ and Chen ZJ. Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses. Science, 2013 Aug: 341(6148):903-6. PMID 23929945
Hasan M, Yan N. Safeguard against DNA sensing: the role of TREX1 in HIV-1 infection and autoimmune diseases. Front Microbiol. 2014 Apr 30;5:193. Review. PMID: 24817865
TREX1-associated autoimmune diseases and glycoimmunology
Another area of interest in our lab is to understand the molecular mechanisms of autoimmune and autoinflammatory diseases. One of the genes we study is TREX1. TREX1/DNase III is an endoplasmic reticulum (ER)-associated negative regulator of innate immunity. Human TREX1 mutations are associated with autoimmune and autoinflammatory diseases. Biallelic (recessive) mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to accumulate, but it is unknown how dominant frame-shift (fs) mutations that encode DNase-active but mislocalized proteins cause disease.
We recently discovered that Trex1-deficiency causes expansion of the lysosome, and that induced an interferon-independent activation of antiviral genes (Hasan et al 2012 Nature Immunology). We also discovered a DNase-independent function of TREX1, in which the TREX1 C-terminus suppresses immune activation through regulation of oligosaccharyltransferase (OST) activity (Hasan and Fermaintt et al 2015 Immunity). We are very interested in understanding how glycan and glycosylation defects could cause immune disorders such as retinal vasculopathy with cerebral leukodystrophy (RVCL, also called Cerebroretinal Vasculopathy, CRV) and systemic lupus erythematosus (SLE).
Hasan M, Koch J, Rakheja D, Pattnaik AK, Brugarolas J, Dozmorov J, Levine B, Wakeland EK, Lee-Kirsch MA and Yan N. Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes. Nature Immunology, 2013 Jan;14(1):61-71. PMID: 23160154.
Hasan M*, Fermaintt CS*, Gao N, Sakai T, Miyazaki T, Jiang S, Li QZ, Atkinson JP, Morse HC III, Lehrman MA and Yan N. Cytosolic nuclease TREX1 C-terminus suppresses immune activation through regulation of oligosaccharyltransferase activity. Immunity, 2015 (in press).
Bacterial evasion of innate immunity and STING biology
STING is an ER-associated membrane protein that is critical for innate-immune sensing of pathogens. STING-mediated activation of the IFN pathway through the TBK1/IRF3 signaling axis involves both cyclic-dinucleotide binding, and its translocation from the ER to vesicles. However, how these events are coordinated, and the exact mechanism of STING activation, remain poorly understood. We found that the Shigella effector protein IpaJ potently inhibits STING signaling by blocking its translocation from the ER to ERGIC, even in the context of dinucleotide binding. Reconstitution using purified components revealed STING translocation as the rate-limiting event in maximal signal transduction. Furthermore, STING mutations associated with autoimmunity in humans were found to cause constitutive ER exit, and to activate STING independent of cGAMP binding. We are interested in investigating an ER-retention and ERGIC/Golgi-trafficking mechanism of STING regulation that is subverted by bacterial pathogens and deregulated in human genetic disease (Dobbs et al 2015 Cell Host & Microbe).
Dobbs N, Burnaevskiy N, Chen D, Gonugunta VK, Alto NM, Yan N. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host & Microbe, 2015, August.