Hozaifa Metwally

The lipopolysaccharide (LPS)-induced endocytosis of Toll-like receptor 4 (TLR4) is an essential step in the production of interferon-β (IFN-β), which activates the transcription of antiviral response genes by STAT1 phosphorylated at Tyr⁷⁰¹ Here, we showed that STAT1 regulated proinflammatory cytokine production downstream of TLR4 endocytosis independently of IFN-β signaling and the key proinflammatory regulator NF-κB. In human macrophages, TLR4 endocytosis activated a noncanonical pho

Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr⁷⁴⁸ as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS)

Threonine phosphorylation promotes inflammatory functions of STAT1 while restricting its interferon (IFN) signaling in innate immune responses. However, it remains unclear whether the restriction of STAT1-mediated IFN signaling conferred by threonine phosphorylation is a ubiquitous mechanism or one that is context-dependent. To address this, we utilized pristane-induced lupus, a prototype IFN-driven systemic autoimmune disease model characterized by the production of high-titer autoantibodies ag

Barrier tissues such as the intestine are constantly challenged by environmental stressors and must adapt to maintain integrity and prevent excessive inflammation. Although traditionally viewed as a proinflammatory effector of interferon (IFN) signaling, STAT1 is shown here to play a protective role in intestinal epithelial cells (IEC) by promoting resilience to damage and restraining IFN-induced cytotoxicity. We identify phosphorylation of threonine 748 (Thr748) on STAT1 as an evolutionarily se

Signal transducer and activator of transcription 1 (STAT1) protein plays a pivotal role in various biological processes especially the regulation of innate and adaptive immune responses. Phosphorylation represents a key step in the activation of STAT1 and its transcriptional outcome.

Immunity is a fundamental aspect of animal biology, defined as the host's ability to detect and defend against harmful pathogens and toxic substances to preserve homeostasis. However, immune defenses are metabolically demanding, requiring the efficient allocation of limited resources to balance immune function with other physiological and developmental needs. To achieve this balance, organisms have evolved sophisticated signaling networks that enable precise, context-specific responses to intern

Abstract Sepsis is caused by infection, especially gram-negative bacteria, followed by an inflammatory cascade leading to cytokine storm. High IL-6 serum level in patients with sepsis is correlated with severity and high mortality. However, the exact pathological mechanism(s) in sepsis regulating high IL-6 expression and how Arid5a, a post-transcriptional regulator of IL-6, is related to exaggerated IL-6 expression are not fully understood yet. We found that Arid5a and IL-6 are more markedly exp

Gut microbiota, the collection of microorganisms harboring the gut of all mammals, are essential for the host’s physiology, metabolism, intestinal homeostasis and immune system development and function. The advancement of technology has allowed a better understanding of the gut microbial communities and their metabolites, how they influence the host’s physiology and homeostasis, and how they also influence the susceptibility of the host to many diseases and disorders.In this mini - review, we wi

Developing defense mechanisms by the host is fundamental to ensure its survival against various microbial pathogens. At the heart of the host defense against microbes is its ability to initiate an immune response to detect and eliminate potential microbial threats. However, in many cases the aberrant immune response is the cause of the host’s clinical symptoms of infections rather than the microbe itself.