Actin Cytoskeleton Dynamics and Type I IFN-Mediated Immune Response: A Dangerous Liaison in Cancer?

Abstract

Chronic viral infection and cancer are closely inter-related and are both characterized by profound alteration of tissue homeostasis. The actin cytoskeleton dynamics highly participate in tissue homeostasis and act as a sensor leading to an immune-mediated anti-cancer and anti-viral response. Herein we highlight the crucial role of actin cytoskeleton dynamics in participating in a viral mimicry activation with profound effect in anti-tumor immune response. This still poorly explored field understands the cytoskeleton dynamics as a platform of complex signaling pathways which may regulate Type I IFN response in cancer. This emerging network needs to be elucidated to identify more effective anti-cancer strategies and to further advance the immuno-oncology field which has revolutionized the cancer treatment. For a progress to occur in this exciting arena we have to shed light on actin cytoskeleton related pathways and immune response. Herein we summarize the major findings, considering the double sword of the immune response and in particular the role of Type I IFN pathways in resistance to anti-cancer treatment.

Keywords: Type I IFN signaling; actin cytoskeleton; innate immune sensors; therapy resistance; viral mimicry.

Figure 1

Schematic representation of IFN-I signaling in infection and cancer. (1) The stimulation of surface, cytosolic, and endosomal pattern recognition receptors (PRRs), by pathogen-associated molecular patterns (PAMPs) during infection or by damage-associated molecular patterns (DAMPs) in cancer, induces IFN-I production. Upon activation, Toll-like receptors (TLRs) signals through TRIF and MyD88, RIG-I-like receptor (RLRs) and NOD-like receptors (NLRs) through MAVS, whereas DNA sensors engage STING. All of these adaptor molecules activate IKKε/TBK1 kinase complex, which in turn triggers the activation of transcription factors IRF3/7 and NF-κB, leading to the production of IFN-α and IFN-β. (2) Once released from infected or cancerous cells, IFN-α and IFN-β act in an autocrine, paracrine, and systemic manner by binding the heterodimeric receptor IFNAR1-2, which in turn activates JAK/STAT pathway leading to the transcription of multiple IFN-stimulated genes (ISGs).

Figure 2

Schematic representation of actin regulatory proteins and their interactions with components of innate immunity. Under homeostatic conditions multiple innate immune sensors are directly or indirectly linked to the actin cytoskeleton. Deregulation of actin cytoskeleton occurring during tumor progression or following viral infections leads to the activation of RLR signaling activation. (a) Focal adhesions kinase (FAK) associates with the actin cytoskeleton in resting cells, but, upon actin reorganization due to virus entry, FAK relocalizes to the mitochondria where it interacts with MAVS, acting as a scaffold between immune signaling and actin cytoskeleton at the mitochondrial membrane. (b) The antiviral sensor RIG-I directly binds F-actin by the N-terminal caspase activation and recruitment domains (CARDs) in resting cells and rearrangements of the actin cytoskeleton lead to its rapid relocalization to the mitochondria, where it interacts with MAVS. (c) Zyxin partially co-localizes with MAVS at mitochondria, where it sustains and stabilizes physical interactions between RLRs and MAVS by its N-terminal domain. (d) Fascin 1 (FSCN1) constitutively binds IKKε, restraining RIG-I signaling pathway. Upon actin reorganization, IKKε is released and associates with TBK1 which in turn phosphorylates IRF3. (e) In uninfected cells, Filamin A sequesters a pool of inactive RNase L in the cytoskeleton preventing viral entry by maintaining a barrier. Viral infection alters actin cytoskeleton and activates RNase L, which cleaves single-stranded viral and host RNAs, leading to the activation of the antiviral response by RIG-I and MDA5. (f) PKR binds gelsolin (GSN) under homeostatic conditions and in turn sequesters it in an inactive conformation, reducing its association with actin. Upon virus entry, PKR is activated by double stranded viral RNA, releases GSN, which can promote actin depolymerization, and activates RLRs signaling. (g) NOD2 binds RAC-1 and co-localizes with F-actin in membrane ruffles. Upon actin cytoskeleton rearrangements such as membrane ruffles disruption, NOD2 is released and can interact with RIP2 leading to NF-kB activation and IL-8 production. The activation of RLR signaling culminates with the production of type I IFNs and inflammatory cytokines.

Figure 3

Actin cytoskeletal deregulation and viral mimicry in cancer. In cancer cells actin cytoskeleton rearrangements constantly occur during tumor progression and could be perceived as an alteration of homeostasis that resembles a viral infection. This viral mimicry induces RLRs signaling activation, culminating with IFN-I production. Depending on the context, acute or chronic IFN-I signaling may have opposite effects in cancer.