RIG-like receptors (RLRs) are cytosolic sensors of viral RNA that respond by inducing the production of the antiviral type I IFNs (Fig. 1). RLRs can recognize double-stranded RNA and RNA-DNA heteroduplexes, which are present in the genomes of RNA viruses and RNA transcripts of RNA and DNA viruses. The two best characterized RLRs are RIG-I (retinoic acid–inducible gene-I) and MDA5 (melanoma differentiation-associated gene 5). Both of these proteins contain two N-terminal caspase recruitment domains that interact with other signaling proteins, an RNA-helicase domain, and a C-terminal domain, the latter two being involved in RNA recognition. RIG-I and MDA5 recognize different sets of viral RNAs that are characteristic of various viruses and not typical of mammalian RNA. For example, MDA5 recognizes long dsRNA (1–6 kb), which is longer than dsRNA that may be formed transiently in normal cells, and RIG-I will only recognize RNA with a 5′ triphosphate moiety, which is not present in mammalian host cell cytosolic mRNA because of the addition of a 7-methylguanosine cap. RIG-I can recognize uncapped, short, single-stranded RNA or dsRNA. MDA-5 can recognize dsRNAs with or without a 5′ cap but only if they are unmethylated at the 2′-O position on the ribose in the first nucleotide adjacent to the cap. Viruses may evade innate immunity by altering these features of viral RNA that are recognized by RLRs. For example, coronaviruses such as SARS CoV-2 can evade RIG-I recognition by utilizing enzymes that generate a 5′ cap on viral RNAs, and they evade MDA-5 mediated antiviral responses by expressing an enzyme that methylates the ribose in the first nucleotide of each viral RNA. RLRs are expressed in a wide variety of cell types, including bone marrow–derived leukocytes and various tissue cells. Therefore, these receptors enable the many cell types that are susceptible to infection by RNA viruses to mount innate immune responses to these viruses. The innate immune mechanisms for recognizing and responding to foreign RNA posed a major challenge to the development of RNA vaccines because those mechanisms can cause severe inflammatory response to and rapid degradation of the vaccine RNA. A key breakthrough leading to the successful development of SARS-CoV-2 RNA vaccines was the modification of vaccine RNA nucleosides, including changing uridines to derivatives called pseudouridines, which reduced detection by innate RNA sensors.

Fig1. Cytosolic retinoic acid–inducible gene (RIG)-like receptors for RNA. The two main receptors of this family, RIG-I and melanoma differentiation-associated gene 5 (MDA5), recognize cytosolic viral RNA and are recruited to mitochondrial and endoplasmic reticulum (ER) membranes by the mitochondrial antiviral-signaling (MAVS) protein. MAVS then forms polymerized aggregates that recruit tumor necrosis factor receptor–associated factor (TRAF) family members, which in turn activate the TBK1 (TANK-binding kinase 1) and IKK (inhibitor of nuclear factor kappa B [NF-κB] kinase) kinases, leading to activation of interferon (IFN) regulatory factor (IRF) and NF-κB transcription factors that induce the expression of type I IFNs. IκB, inhibitor of NF-κB.

On binding viral dsRNA, the RLRs are recruited to the outer mitochondrial membrane by the MAVS (mitochondrial antiviral-signaling) protein (see Fig. 1). This leads to a self perpetuating mechanism whereby MAVS polymerizes to form high-molecular-weight filamentous aggregates that induce other MAVS molecules to polymerize. The MAVS aggregates recruit TRAF family members that are required for the activation of the TBK1 and IKK kinases. TBK1 phosphorylates and activates IRF3 and IRF7 and IKK activates NF-κB; these transcription factors induce production of type I IFNs.

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شعبة التوجيه الديني النسوي تنظم مسابقة ثقافية بذكرى ولادة السيدة المعصومة (عليها السلام)

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قسم الشؤون الفكرية يقيم معرضًا وثائقيًا ضمن مهرجان (الشهيد) في جامعة الكوفة

قسم الشؤون الدينية يشهد إقبالًا واسعًا من المؤمنين لتنظيم عقود الزواج

المزيد

الآخبار الصحية

دواء جديد يحمي القلب ويعزز علاج السرطان في آن واحد

سر غذائي بسيط لحماية القلب مع التقدم في العمر

علامات تشير إلى اختلال عمل الغدة الدرقية

السمنة واللقاحات.. دراسة تكشف تأثيراً سلبياً

المزيد

الآخبار التكنلوجية

البعوض في آيسلندا إشارة مبكرة على تحولات بيئية في القطب الشمالي

صاروخ يطلق قمرا اصطناعيا في مدار خاطئ

"أوبن إيه آي" تطلق نموذجا للعلوم الحيوية واكتشاف الأدوية

تفوق على البشر.. روبوت يحطم الرقم القياسي لسباق نصف ماراثون !

المزيد

مواضيع ذات صلة

Antigen Capture and the Functions of Antigen-Presenting Cells

Cytosolic DNA Sensors and the STING Pathway

Inflammasomes

Antigens

NOD-Like Receptors: NOD1 and NOD2

Recognition of Microbes and Damaged Tissue by the Innate Immune System

Overview of Innate Immunity

Transplantation of Tissues and Organs

Rh Blood Types

O-A-B Blood Types

Allergy and Hypersensitivity

The Antiviral Response