Downregulation of a cell polarity protein potentiates Chikungunya Virus infection in host cells

Abstract

Downregulation of the host cell pro-apoptotic pathways confers a selective advantage to viral pathogens, and many viruses interfere with such regulatory mechanisms in order to enhance their propagation in infected cells. The Scribble cell polarity complex, which is composed of multiple adapter proteins including human Scribble, Dlg and MAGI, controls a variety of host cell functionalities including apoptosis, morphology, polarity, signaling and migration. In the recent years, components from several viral pathogens, including oncogenic viruses, have been found to associate with and modulate the activities of this complex, particularly that of the pro-apoptotic protein Scribble. Here, we establish a critical role for the downregulation of Scribble expression for the potentiation of Chikungunya Virus (CHIKV) infection. CHIKV is a well-known mosquito-borne alphavirus, which has caused outbreaks in more than 100 countries and constitutes a global health hazard. While the majority of the CHIKV proteome is well characterized, the role of a small structural protein 6K, and its transframe variant, TF, which is generated from the 6K sequence by ribosomal slippage and frameshifting, is not established as yet. We show that TF triggers the punctation, ubiquitination and degradation of Scribble during CHIKV infection, and that the downregulation of Scribble during CHIKV infection. We show that the association of TF with the PDZ domains of Scribble is mediated through a PDZ-domain binding motif at the C-terminus of TF. Thus, our work establishes a role for the downregulation of Scribble in alphavirus infections for the first time, while allocating a novel role in host modulation to the mysterious 6K/TF component of alphaviruses.