PTEN-L promotes type I interferon responses and antiviral immunity

Abstract

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a well-known tumor suppressor that acts as a dual-specificity phosphatase and is frequently mutated in human cancer. Our previous work has demonstrated that PTEN also plays a vital role in type I interferon responses and antiviral innate immunity. Recently, a translational variant of PTEN with a long N-terminal extension (PTEN-L) has been discovered that is secreted into the extracellular environment and enters recipient cells, where it exerts a phosphatase function antagonistic to PI3K/Akt signaling and tumorigenesis. In this study, we demonstrate that PTEN-L promotes type I interferon responses and antiviral innate immunity during viral infection in a phosphatase activity-dependent manner. Compared with canonical PTEN, PTEN-L also exerts its antiviral function when it is applied exogenously in protein form. This finding was confirmed in cell cultures and mouse infection models. Furthermore, PTEN-L enhances the responses of both type I interferon and proinflammatory cytokines, thus suggesting that PTEN-L might possess additional functions compared with those of PTEN. Thus, the antiviral function of PTEN-L may open an avenue for the use of PTEN-L in antiviral therapy, particularly in patients with PTEN-deficient tumors.

PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance

“…Interestingly, a recent report suggests that PTENα induces antiviral immunity, resulting in reduced HSV infection and increased clearance by aggravating type 1 IFN responses 53 . In our studies, we did not observe any inhibitory impact of PTENα production by HSV-P10 on virus infection and/or replication.…”

PTEN‐deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells

“…Emerging evidence indicates that PTEN may have additional lipid phosphatase independent functions that are independent of the PI3K/AKT pathway, including those affecting tumor growth through modulation of the immune response and tumor microenvironment (TME) . In immune cells, PTEN is critical for cell maturation and activation .…”

“…In immune cells, PTEN is critical for cell maturation and activation . More recently, the secreted PTEN long protein (PTEN‐L) was also reported to be the key in activating the antiviral type I interferon (IFNI) response . In addition, PTEN regulates the NF‐kB pathway, which underlies several immune response pathways but can be protumorigenic in the TME .…”

PTENα regulates endocytosis and modulates olfactory function

“…Moreover, it has been reported to play different roles at different stages of brain development, including neuron differentiation, migration, and synaptic plasticity modulation, mostly depending on its regulation on downstream target Akt (47,48). PTENa is recently shown to play a diversity of biologic roles in several recent studies, including regulation of mitochondria metabolism (21), regulation of spatial learning and contextual fear memory (22), cardiac homeostasis maintenance and regulation of mitophagy (23,24), and regulation of type I IFN responses and antiviral immunity (25). PTENa is expressed in many types of tissue, and expression of PTENa in the brain is high.…”

“…PTENa translates from the 59UTR region of the same mRNA as PTEN, containing an evolutionarily conserved 173-aa N-terminal extension (20,21). Recently, PTENa is shown to play important roles in maintenance of mitochondrial structure and energy metabolism (21), modulation of hippocampal long-term potentiation and processes of learning and memory (22), regulation of cardiac homeostasis and mitophagy (23,24), and promotion of type I IFN responses and antiviral immunity (25). However, it likely has other biologic functions that have not been characterized.…”