Essential contribution of the JAK/STAT pathway to carcinogenesis, lytic infection of herpesviruses and pathogenesis of COVID‑19 (Review)

Abstract

The intracellular pathway of Janus kinase/signal transducer and activator of transcription (JAK/STAT) and modification of nucleosome histone marks regulate the expression of proinflammatory mediators, playing an essential role in carcinogenesis, antiviral immunity and the interaction of host proteins with Herpesviral particles. The pathway has also been suggested to play a vital role in the clinical course of the acute infection caused by severe acute respiratory syndrome coronavirus type 2 (SARS‑CoV‑2; known as coronavirus infection‑2019), a novel human coronavirus initially identified in the central Chinese city Wuhan towards the end of 2019, which evolved into a pandemic affecting nearly two million people worldwide. The infection mainly manifests as fever, cough, myalgia and pulmonary involvement, while it also attacks multiple viscera, such as the liver. The pathogenesis is characterized by a cytokine storm, with an overproduction of proinflammatory mediators. Innate and adaptive host immunity against the viral pathogen is exerted by various effectors and is regulated by different signaling pathways notably the JAK/STAT. The elucidation of the underlying mechanism of the regulation of mediating factors expressed in the viral infection would assist diagnosis and antiviral targeting therapy, which will help overcome the infection caused by SARS‑CoV‑2.

Keywords: EBV; JAK/STAT; KSHV; SARS‑CoV‑2; carcinoma; herpesviruses.

Figure 1.

Scheme of action pattern of gene expression regulated by JAK/STAT pathway. The cellular responses elicited by three representing cytokines, IL-6, IFN-gamma and IFN alpha/beta are illustrated. The receptors associated JAKs are recruited and activated on receptor ligation, then different STATs are phosphorylated and homo- or heterodimerized. The dimerized STATs translocate to nuclei, binding regulatory elements upstream of coding portion of genes and initiate their transcription (11). JAK, Janus kinase; STAT, signal transducer and activator of transcription; IRF, interferon regulatory factor.

Figure 2.

Effect of STATs pathway interacting with herpesviruses EBV and KSHV during lytic cycle and interferon signaling. (A) High level of STAT3 activated by IL-6 on binding with its cognate receptor regulates EBV entry to lytic cycle; it is inhibited by the protein PIAS3. (B) The JAK/STAT pathway downstream of type I interferon counteracted by herpesviruses EBV and KSHV encoded products; IFNAR binds IFN-alpha and beta, then recruited JAK1 and TYK2, the latter is inhibited by a EBV latent protein, LMP1, while the heterotrimer STAT1-STAT2-IRF9 formed after activation of JAK1/TYK2 is inhibited by EBV kinase BGLF4 and by KSHV encoded vIRF2. STAT, signal transducer and activator of transcription; EBV, Epstein Barr virus; KSHV, Kaposi sarcoma-associated herpesvirus; PIAS3, protein inhibitor of activated STAT3; JAK, Janus kinase; IFNAR, interferon alpha/beta receptor; TYK, tyrosine kinase; vIRF, viral interferon regulatory factor.

Figure 3.

Linear clustering of JAK2 motifs and role of abnormal JAK/STAT signaling in carcinogenesis. (A) The JAK2 molecule contains motifs of FERM required for lower Michaelis constant (Km; the concentration of saturated substrate in case of the half of maximum catalytic speed of an enzyme being reached) of JAK2 (V617F) towards substrates, SH2, pseudo-PTK and the functional PTK. The pseudo-PTK domain starting with amino acid residue 604 is identical in human and mouse. The mutation on 617 position of amino acid sequence is responsible for hemopoietic disorders described. (B) The impact of aberrant JAK/STAT pathway in carcinogenesis. High expression of STAT1 downstream of IFN-g signaling induces PD-L1 expression, enabling the tumor cells to evade host antitumor immunity. Mutant JAK2 with the lesion of V617F alters STAT3 signaling and fused protein BCR/ABL expressed from the translocated gene on Ph1 chromosome induces abnormal STAT5 signaling to enhance transcription of cyclins D1, D2, E and anti-apoptotic regulator Bcl_xL, to promote cancer initiation. JAK, Janus kinase; STAT, signal transducer and activator of transcription; FERM, 4.1/ezrin/radixin/moesin; SH2, Src homolog 2; PTK, protein tyrosine kinase; PD-L1, programmed cell death ligand 1; Ph, Philadelphia; Bcl xL, B-cell lymphoma-extra large.

Figure 4.

Schematic pattern of genomic composition of SARS-CoV-2. (A) The arrangement of exons within SARS-CoV-2 genome is indicated and referred to the text. (B) The genomic products of SARS-CoV-2 target to several components of the axis of JAK/STAT pathway. SARS-CoV-2, severe acute respiratory syndrome coronavirus type 2; JAK, Janus kinase; STAT, signal transducer and activator of transcription; IFNAR, interferon alpha/beta receptor; IRF, interferon regulatory factor; ORF, open reading frame.