Viral manipulation of cell polarity signalling.

Cell polarity refers to the asymmetric distribution of biomacromolecules that enable the correct orientation of a cell in a particular direction. It is thus an essential component for appropriate tissue development and function. Viral infections can lead to dysregulation of polarity.

Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1.

Scribble (Scrib) is a multidomain polarity protein and member of the leucine-rich repeat and PDZ domain (LAP) protein family. A loss of Scrib expression is associated with disturbed apical-basal polarity and tumor formation. The tumor-suppressive activity of Scrib correlates with its membrane localization.

Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis.

G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections.

Viral subversion of the cell polarity regulator Scribble.

Scribble is a scaffolding protein that regulates key events such as cell polarity, tumorigenesis and neuronal signalling. Scribble belongs to the LAP family which comprise of 16 Leucine Rich Repeats (LRR) at the N-terminus, two LAP Specific Domains (LAPSD) and four PSD-95/Discs-large/ZO-1 (PDZ) domains at the C-terminus. The four PDZ domains have been shown to be key for a range of protein-protein interactions and have been identified to be crucial mediators for the vast majority of Scribble interactions, particularly via PDZ Binding Motifs (PBMs) often found at the C-terminus of interacting proteins.

Structural insight into the Scribble PDZ domains interaction with the oncogenic Human T-cell lymphotrophic virus-1 (HTLV-1) Tax1 PBM.

Scribble (Scrib) is a highly conserved cell polarity regulator that harbours potent tumour suppressor activity and plays an important role in cell migration. Dysregulation of polarity is associated with poor prognosis during viral infections. Human T-cell lymphotrophic virus-1 (HTLV-1) encodes for the oncogenic Tax1 protein, a modulator of the transcription of viral and human proteins that can cause cell cycle dysregulation as well as a loss of genomic integrity.

Molecular basis of Tick Born encephalitis virus NS5 mediated subversion of apico-basal cell polarity signalling.

The Scribble (Scrib) protein is a conserved cell polarity regulator with anti-tumorigenic properties. Viruses like the Tick-born encephalitis virus (TBEV) target Scribble to establish a cellular environment supporting viral replication, which is ultimately associated with poor prognosis upon infection. The TBEV NS5 protein has been reported to harbour both an internal as well as a C-terminal PDZ binding motif (PBM), however only the internal PBM was shown to be an interactor with Scribble, with the interaction being mediated via the Scribble PDZ4 domain to antagonize host interferon responses.

Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble.

Scribble is a highly conserved regulator of cell polarity, a process that enables the generation of asymmetry at the cellular and tissue level in higher organisms. Scribble acts in concert with Disc-large (Dlg) and Lethal-2-giant larvae (Lgl) to form the Scribble polarity complex, and its functional dysregulation is associated with poor prognosis during viral infections. Viruses have been shown to interfere with Scribble by targeting Scribble PDZ domains to subvert the network of interactions that enable normal control of cell polarity via Scribble, as well as the localisation of the Scribble module within the cell.

Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain.

SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure. However, the molecular basis of these symptoms remains unclear. SARS-CoV-1 E protein interferes with control of cell polarity and cell-cell junction integrity in human epithelial cells by binding to the PALS1 PDZ domain, a key component of the Crumbs polarity complex.

Structural insight into tanapoxvirus-mediated inhibition of apoptosis.

Premature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double-stranded DNA virus belonging to the poxviridae that causes mild monkeypox-like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L.