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Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
RNA sensing occurs through the activity of retinoic acid gene-I (RIG-I)-like receptors (RLR). These classically serve to sense the presence of RNA species generated during viral infection and can detect both single (ss) and double-stranded (ds) RNA. Three RLRs have been described: RIG-I, melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). RIG-I and MDA5 consist of two amino-terminal caspase-associated recruitment domains (CARDs), which signal the presence of RNA species that bind a DEAD box (N-terminal) helicase/ATPase domain that is normally repressed by a carboxy-terminal regulatory domain (CTD). RIG-I detects short dsRNA species that possess 5′ end di- and tri-phosphorylated sequences generated by oligoadenylate synthetase (OAS) and RNaseL processing of RNA viruses or Pol III generated dsRNA species from dsDNA viruses. Upon RNA binding and ubiquitination by Riplet and TRIM25, RIG-I binds mitochondrial antiviral-signaling protein (MAVS) to activate two pathways, which together converge on the production of myeloid interferons: TANK-binding kinase-1 (TBK1) and IκB kinase epsilon (IKKe) phosphorylation and activation of IRF3 and IRF7 or induction of NF-κB on repression of IκB. The interferons induced are secreted and activate IFN receptor signaling and the induction of interferon-stimulated genes through the activation of STAT1, STAT2, and IRF9. MDA-5 senses long dsRNA species in a ubiquitin-independent pathway. The third member of the RLR family is less well understood; it binds RNA species but lacks a CARD domain.
JAK-STAT pathway: Testicular development, spermatogenesis and fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
The JAK-STAT pathway has been extensively studied in a wide range of organisms from slime molds to mammals. In mammals, it was originally identified through cytokine (IFNα, IFNγ) and growth factor–induced signaling (7) by which it regulates various cellular events such as cell proliferation, differentiation and apoptosis (1). The components of the JAK-STAT pathway have been identified in a wide range of organisms including Drosophila melanogaster, Caenorhabditis elegans and mammals. In mammals, there are more than 50 cytokine-like molecules that mediate JAK-STAT signaling. The diverse functions of this pathway in different cells are regulated by four JAK family members, i.e., JAK1, JAK2, JAK3 and TYK2, and seven STAT family members, i.e., STAT1, STAT2, STAT3. STAT4, STAT5a, STAT5b and STAT6 (8) (Table 15.1). Because of the numerous JAK and STAT homologues, study of the system is more complex (3,9).
Human Parainfluenza Virus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Eric T. Beck, Kelly J. Henrickson
In addition to the six common HPIV proteins, some of these viruses also produce several accessory proteins. The C protein is a nonstructural protein that is packaged within HPIV-1, -2, and -3 virions and is thought to play a role in regulating viral transcription and RNA replication. Studies have shown that the C protein can bind to the L protein and that it may be involved in decreasing viral RNA synthesis.51–55 It also appears to regulate the amount of viral double-stranded RNA (dsRNA) present in the cell, which can accumulate during replication of RNA viruses. Accumulation of viral dsRNA can lead to degradation of viral RNA (ssRNA) via the RNAi pathway, thus preventing its accumulation is of critical importance to virus survival.56 Finally, HPIV C proteins can disrupt the function of the STAT1 and/or STAT2 proteins through ubiquitination/degradation, preclusion of phosphorylation, and/or prevention of nuclear translocation.57–63 STAT1 and STAT2 proteins are major components of the IFN pathway, and their alteration/destruction ultimately blocks interferon signaling and the host apoptotic response, allowing the virus to avoid the host immune response for a longer period of time.64 Experimental data indicate that the V protein, like the C protein, may be involved in regulating the interferon signaling pathway. The V protein of HPIV-2 has been implicated in the ubiquitination and eventual degradation of the STAT2 protein.65–67 In addition to the C and V proteins, HPIVs also express other accessory proteins, such as W, I, and D proteins. The exact function of these proteins is not fully understood, but they all appear to play some role in the regulation of RNA synthesis.5
Hematopoietic stem cell transplantation in systemic autoinflammatory diseases - the first one hundred transplanted patients
Published in Expert Review of Clinical Immunology, 2022
Sara Signa, Gianluca Dell’Orso, Marco Gattorno, Maura Faraci
STAT2 acts as both positive and negative regulator of IFN-I signaling, an unique behavior exemplified by its monogenic defects. Patients with AR STAT2 deficiency present increased susceptibility to severe and/or recurrent viral disease. Conversely, homozygous missense variants affecting the same arginine 148 residue of STAT2 lead to a severe early-onset type I interferonopathy, as described in three children [73–75]. The latter phenotype is characterized by a very early onset of systemic inflammation and multi-organ dysfunction, including recurrent fever, hepatosplenomegaly, intracranial calcifications, cytopenia with marked thrombocytopenia, raised ferritin, elevated liver enzymes [73] and skin ulcerations [74]. Disease presents a partial response to steroids and JAK inhibitors, but the neurological damage tends to progress despite medical treatment. HSCT is described in one patient, who died 15 days after HSCT for sepsis [73]. It has to be noted that general conditions of the patient were already critical at the time of the transplant, and further experience is required to understand if HSCT may correct the STAT2 GOF patients’ phenotype.
Type I interferon detection in autoimmune diseases: challenges and clinical applications
Published in Expert Review of Clinical Immunology, 2021
Vassilis E. Papadopoulos, Charalampos Skarlis, Maria-Eleftheria Evangelopoulos, Clio P. Mavragani
Type I IFNs transduce their signal through binding to IFNα/β receptor (IFNAR) (composed by two subunits, IFNAR1 and IFNAR2), leading to autophosphorylation of receptor-associated kinases, namely Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which are attached to IFNAR1 and IFNAR2, respectively. This leads to the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2, which consequently assemble, forming the STAT1/2 heterodimer. The latter binds to IRF9, leading to the formation of the IFN-stimulated gene factor 3 (ISGF3). ISGF3 translocates to the nucleus where it binds to the interferon-stimulated response elements (ISRE) inducing their transcription and the subsequent upregulation of hundreds of interferon-stimulated genes (ISG) also known as IFN signature [9,11,12] (Figure 3).
Zika virus pathogenesis and current therapeutic advances
Published in Pathogens and Global Health, 2021
Caroline Mwaliko, Raphael Nyaruaba, Lu Zhao, Evans Atoni, Samuel Karungu, Matilu Mwau, Dimitri Lavillette, Han Xia, Zhiming Yuan
The NS5 protein is the largest (approximately 900 amino acids) and most conserved of the flavivirus proteins. The NS5 protein contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis [60]. NS5 is also an IFN antagonist that degrades STAT2, which in turn, limits type I IFN signaling and leads to increased viral replication. STAT2 is a signaling molecule required in the IFN I pathway. The mechanism of STAT2 degradation in ZIKV by the NS5 protein is distinct from that in DENV. Expression of ZIKV NS5 alone results in STAT 2 degradation and does not require maturation of the N terminus of NS5 and does not involve UBR4 [61]. The interaction is also host-specific since NS5 is unable to degrade murine STAT2, leading to susceptibility to ZIKV infection in immunocompetent mice. ZIKV has been shown to bind and degrade STAT2 through proteasomal degradation. Antagonism of STAT1 and STAT2 phosphorylation results in ZIKV disease [62].