Autophagy, the innate immune response and cancer.

Autophagy is a cellular degradation and recycling system, which can interact with components of innate immune signalling pathways to enhance pathogen clearance, in both immune and nonimmune cells. Whilst this interaction is often beneficial for pathogen clearance, it can have varying outcomes in regard to tumorigenesis. Autophagy and the innate immune response can have both pro- and antitumorigenic effects at different stages of tumorigenesis due to the plastic nature of the tumour microenvironment (TME). Although both of these components have been studied in isolation as potential therapeutic targets, there has been less research concerning the interaction between autophagy and the innate immune response within the TME. As the innate immune response is critical for the formation of an effective antitumour adaptive immune response, targeting autophagy pathways in both tumour cells and innate immune cells could enhance tumour clearance. Within tumour cells, autophagy pathways are intertwined with pattern recognition receptor (PRR), inflammatory and cell death pathways, and therefore can alter the immunogenicity of the TME and development of the antitumour immune response. In innate immune cells, autophagy components can have autophagy-independent roles in functional pathways, and therefore could be valuable targets for enhancing immune cell function in the TME and immunotherapy. This review highlights the individual importance of autophagy and the innate immune response to tumorigenesis, and also explains the complex interactions between these pathways in the TME.

Varicella-Zoster Virus ORF63 Protects Human Neuronal and Keratinocyte Cell Lines from Apoptosis and Changes Its Localization upon Apoptosis Induction.

There are many facets of varicella-zoster virus (VZV) pathogenesis that are not fully understood, such as the mechanisms involved in the establishment of lifelong latency, reactivation, and development of serious conditions like postherpetic neuralgia (PHN). Virus-encoded modulation of apoptosis has been suggested to play an important role in these processes. VZV open reading frame 63 (ORF63) has been shown to modulate apoptosis in a cell-type-specific manner, but the impact of ORF63 on cell death pathways has not been examined in isolation in the context of human cells. We sought to elucidate the effect of VZV ORF63 on apoptosis induction in human neuron and keratinocyte cell lines. VZV ORF63 was shown to protect differentiated SH-SY5Y neuronal cells against staurosporine-induced apoptosis. In addition, VZV infection did not induce high levels of apoptosis in the HaCaT human keratinocyte line, highlighting a delay in apoptosis induction. VZV ORF63 was shown to protect HaCaT cells against both staurosporine- and Fas ligand-induced apoptosis. Confocal microscopy was utilized to examine VZV ORF63 localization during apoptosis induction. In VZV infection and ORF63 expression alone, VZV ORF63 became more cytoplasmic, with aggregate formation during apoptosis induction. Taken together, this suggests that VZV ORF63 protects both differentiated SH-SY5Y cells and HaCaT cells from apoptosis induction and may mediate this effect through its localization change during apoptosis. VZV ORF63 is a prominent VZV gene product in both productive and latent infection and thus may play a critical role in VZV pathogenesis by aiding neuron and keratinocyte survival.IMPORTANCE VZV, a human-specific alphaherpesvirus, causes chicken pox during primary infection and establishes lifelong latency in the dorsal root ganglia (DRG). Reactivation of VZV causes shingles, which is often followed by a prolonged pain syndrome called postherpetic neuralgia. It has been suggested that the ability of the virus to modulate cell death pathways is linked to its ability to establish latency and reactivate. The significance of our research lies in investigating the ability of ORF63, a VZV gene product, to inhibit apoptosis in novel cell types crucial for VZV pathogenesis. This will allow an increased understanding of critical enigmatic components of VZV pathogenesis.