Wednesday, August 14, 2013

Viral DNA? Lets do a STING operation


    The human immune system has been well equipped and has evolved overtime to compete the invader (in this case pathogens). The most important point is how does a cell recognize there is an invasion in the first place. Well, every single entity in the biological system comes up with a unique signature (You can call it a biological signature) which can be recognized. The molecules associated with pathogens are referred as pathogen-associated molecular patterns (PAMPs). There are sensors for every different kind of PAMPs that enable the immune system to defend. The pattern recognition receptors (PRRs) are responsible for recognition. Some of the most well known PRRs include

Fig 1: Model of PRRs action
1. Toll-like receptors(TLRs)
2. NOD-like receptors (NLRs)
3. RIG-I-like receptors (RLRs)
4. C-type lectin receptors (CLRs). 

    Imagine this scenario. A DNA virus (say for example HSV-1), has injected a genetic material into the cell. The most important event, from cellular immunological point of view is to sense the genetic material. DNA in cytoplasm is a definitive indicator of invasion, as DNA is not seen in the cytoplasm. This is in opposition to RNA where the cell has to make a distinction of self and non self. The point of this post is to look into how DNA is sensed leading to a long series of events.

Table 1: proposed sensors for Cytosolic DNA.
     To begin with, there is a huge scarcity of studies that aim to understand DNA sensing in cells. DNA can be found in scenario's of Nuclear damage or viral invasion all of which signifies damage. There are several receptors proposed as cytosolic DNA sensor. See table 1.The most recently discovered factor is cGAS. In this post am elaborating only on cGAS as DNA sensor.

Fig 2: Mechanism of responding to DNA in cytosol
       I want to digress here. Interferon's (Originally named so, for its ability to interfere with viral replication) are classified into 2 types based on the receptor specificity. Interferon type-I consists of all the interferon which are structurally related and bind to a common hetero-dimeric receptor IFNAR (Interferon-α/β receptor) consisting of two units- IFNAR1 and IFNAR2. Interferon type-II consist of a single entity IFNγ. STING refers to "Simulator of Interferon genes". STING is involved in regulation and promotion Interferon type-I mediators.Structural analysis has shown that the STING can be bound by cyclic di-GMP (c-di-GMP), which is a bacterial secondary mesenger and a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP). STING is present in the endoplasmic reticulum.
Fig 3: Activation of cGAS. Source
     A very recent structural analysis shows that a very specific isomer of cGAMP, namely c[G(2',5') pA(3',5')p], was produced by cGAS. hSTING (Human STING) is composed of a N-terminal transmembrane domain (amino acid 1–154), a central globular domain (aa 155–341), and a C-terminal tail (aa 342–379). It has been shown convincingly that the STING opts a V-shaped conformation which allows binding of DNA ligand. The binding induces a conformational change in STING structure, thereby allowing access to active site which is a nucleotide-binding pocket.

      You may ask, what is the big deal? cGAS is just one more sensor and a player among other members. And definitely, this isn't the only one. Though there are other molecules demonstrated to be involved (See table 1). However, cGAS has been the most convincing of all. Based on back to back Nature Papers by Veit Hornung etal, comments "With this finding we have the first evidence for a mechanistic and evolutionary link between DNA- and RNA-induced immune reactions" and "In a second study, published simultaneously in Nature, we also determined the structure of the dinucleotide, and show that it represents a previously unknown form of this class of signaling molecule". Source
Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, Lu Y, Miyagishi M, Kodama T, Honda K, Ohba Y, & Taniguchi T (2007). DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature, 448 (7152), 501-5 PMID:17618271

Yang PAn HLiu XWen MZheng YRui YCao X. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenindependent pathway. Nat Immunol. 11(6):487-94. PMID:20453844

Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, Serganov AA, Liu Y, Jones RA, Hartmann G, Tuschl T, Patel DJ. Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase.Cell. 2013 May 23;153(5):1094-107. PMID: 2364784

Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, Hopfner KP, Ludwig J, & Hornung V (2013). cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING. Nature, 498 (7454), 380-4 PMID: 23722158

Diner EJ, Burdette DL, Wilson SC, Monroe KM, Kellenberger CA, Hyodo M, Hayakawa Y, Hammond MC, & Vance RE (2013). The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell reports, 3 (5), 1355-61 PMID: 23707065

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