PDZ proteins are expressed and regulated in antigen-presenting cells and are targets of influenza A virus

Abstract

In this work, we identified the expression, regulation, and viral targeting of Scribble and Dlg1 in antigen-presenting cells. Scribble and Dlg1 belong to the family of PDZ (postsynaptic density (PSD95), disc large (Dlg), and zonula occludens (ZO-1)) proteins involved in cell polarity. The relevance of PDZ proteins in cellular functions is reinforced by the fact that many viruses interfere with host PDZ-dependent interactions affecting cellular mechanisms thus favoring viral replication. The functions of Scribble and Dlg have been widely studied in polarized cells such as epithelial and neuron cells. However, within the cells of the immune system, their functions have been described only in T and B lymphocytes. Here we demonstrated that Scribble and Dlg1 are differentially expressed during antigen-presenting cell differentiation and dendritic cell maturation. While both Scribble and Dlg1 seem to participate in distinct dendritic cell functions, both are targeted by the viral protein NS1 of influenza A in a PDZ-dependent manner in dendritic cells. Our findings suggest that these proteins might be involved in the mechanisms of innate immunity and/or antigen processing and presentation that can be hijacked by viral pathogens.

Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

“…The NS1 PBM binding also colocalizes MAGI-1 in these puncta, potentially perturbing its regulation of interferon-β signaling [232]. The Dlg/Scrib interaction has also recently been suggested to be involved in dendritic cell maturation, and to be targeted there by NS1, thus potentially leading to evasion of both innate and acquired immune systems [219,233].…”

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

“…More recently, we have demonstrated the expression and regulation of Scribble and Dlg1 in human APCs, including monocytes, macrophages (Mf), and DCs; both proteins are up-regulated in mDCs compared with immature DCs but do not colocalize in any of these conditions, suggesting that Scribble and Dlg1 may participate in distinct functions during DC maturation (26). Furthermore, similarly to spinophilin, Scribble relocalizes to the plasma membrane in mDC and to the IS during Ag presentation.…”

“…The IAV NS1 protein with the most virulent PDZbm, ESEV (NS1_ESEV), is able to target Scribble and Dlg1 in a PDZ-dependent fashion in epithelial cells, where the targeting of Scribble induces its relocation from the cytosol to the perinuclear region, leading to the destabilization of the tight junction and the protection of infected cells from apoptosis, thus enhancing IAV replication (68,69). We have recently demonstrated that the NS1_ESEV also targets Scribble and Dlg1 in DCs (26). NS1_ESEV strongly colocalizes with Dlg1 and Scribble in large cumuli in the cytosol when compared with PDZbm-lacking variants or other NS1 PDZbm specificities.…”

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

“…15 Moreover, we have recently reported the expression of both Scrib and Dlg1 in human APCs including DCs, M , and monocytes. 16 Notably, both Scrib and Dlg1 augment their expression with the maturation process in DCs, suggesting that these proteins are involved in fundamental functions of DC biology. 16 Nowadays, there is evidence that polarity is also relevant for DC functions.…”

“…16 Notably, both Scrib and Dlg1 augment their expression with the maturation process in DCs, suggesting that these proteins are involved in fundamental functions of DC biology. 16 Nowadays, there is evidence that polarity is also relevant for DC functions. In fact, pivotal events for T cell priming such as MHC-II expression or IL-12 secretion toward T cell depend on DC polarization events.…”