Scrib and Dlg1 polarity proteins regulate Ag presentation in human dendritic cells

Abstract

We recently reported, for the first time, the expression and regulation of the PDZ polarity proteins Scrib and Dlg1 in human APCs, and also described the viral targeting of these proteins by NS1 of influenza A virus in human dendritic cells (DCs). Scrib plays an important role in reactive oxygen species (ROS) production in Mϕs and uropod formation and migration in T cells, while Dlg1 is important for T cell downstream activation after Ag recognition. Nevertheless, the functions of these proteins in human DCs remain unknown. Here, we knocked‐down the expression of both Scrib and Dlg1 in human DCs and then evaluated the expression of co‐stimulatory molecules and cytokine production during maturation. We demonstrated that Scrib is necessary for adequate CD86 expression, while Dlg1 is important for CD83 up‐regulation and IL‐6 production upon maturation, suggesting that Scrib and Dlg1 participate in separate pathways in DCs. Additionally, both proteins are required for adequate IL‐12 production after maturation. Furthermore, we showed that the inefficient maturation of DCs induced by Scrib or Dlg1 depletion leads to impaired T cell activation. Our results revealed the previously unknown contribution of Scrib and Dlg1 in human DCs pivotal functions, which may be able to impact innate and adaptive immune response.

Identification of Host PDZ-Based Interactions with the SARS-CoV-2 E Protein in Human Monocytes

“…In epithelial cells, Scrib forms a complex that localizes to the basolateral membrane which is essential for the establishment of cell polarity [ 34 ], whereas synaptic terminals regulate vesicle clustering and release [ 35 ]. Scrib also participates in the organization of the immunological synapse in T cells [ 7 ], facilitates the formation of phagosome in macrophages [ 10 ], and participates in the maturation and antigen presentation process of dendritic cells [ 36 ].…”

Distinct Transcriptional Profile of PDZ Genes after Activation of Human Macrophages and Dendritic Cells

“…Recently, in addition to our group, other researchers gained an insight into Scrib and Dlg1, which are two PDZ proteins governing apicobasal epithelial cell polarity (ABCP) in the central signaling pathways of Mφ and DCs in mice and humans [11][12][13]19]. Scrib and Dlg1 are expressed and regulated in human APCs, including monocytes, Mφ, and DCs, and play key roles in the expression of co-stimulatory molecules and IL-12 production in DCs where both proteins can be targeted by Inlfuenza A virus [12,13]. Owing to this knowledge and the evolutionary conservation of these scaffolding proteins, we hypothesized that more members would support several cellular processes involved in the activation of APCs.…”

“…Recently, the relevant roles of some PDZ proteins have been demonstrated in APCs [11][12][13]. The scaffold function of the polarity protein, Scrib, is required for the correct assembly of the NADPH oxidase (NOX) complex in a PDZ domain-dependent manner and the generation of NOX-induced reactive oxygen species (ROS) in macrophages, which are indispensable for pathogen destruction [11].…”

“…The scaffold function of the polarity protein, Scrib, is required for the correct assembly of the NADPH oxidase (NOX) complex in a PDZ domain-dependent manner and the generation of NOX-induced reactive oxygen species (ROS) in macrophages, which are indispensable for pathogen destruction [11]. In addition, Scrib and Dlg1 play important roles during antigen presentation as contributors to the expression of co-stimulatory molecules and IL-12 production during DC maturation, and can be targeted by influenza A virus [12,13]. Consequently, both proteins might be involved in the regulation of both innate and adaptive immune responses elicited by myeloid immune cells.…”