Biology subjects

Senay, T. E.

Publications and source records attributed to Senay, T. E..

2 recordsLinked to original sources

bioRxiv2025

A short intrinsically disordered domain of MCPyV ALTO regulates host TBK1 signaling and MCPyV latency

Merkel Cell Polyomavirus (MCPyV) is an oncogenic human polyomavirus that latently infects most adults. Although the causative link between MCPyV and Merkel Cell Carcinoma (MCC) is well established, the molecular mechanisms that govern viral latency and prevent oncogenic progression remain poorly understood. We previously reported that the MCPyV early region protein ALTO is a key modulator of the STING-TBK1 signaling axis, enabling the virus to co-opt host innate immune pathways to suppress excessive viral replication and promote latency over transformation. In this study, we expand on this model by identifying a short, essential domain within ALTO that is required for TBK1 activation. This domain, which we term LIT (Lost in Tau), is necessary for ALTO-TBK1 interaction but dispensable for ALTO trafficking and its interactions with STING or Src. When expressed alone, the LIT domain functions as a dominant negative inhibitor of wild-type ALTO, competitively blocking TBK1 activation through a novel TBK1 interaction domain. Deletion of the LIT domain from ALTO not only abolishes TBK1 interaction and downstream phosphorylation but also eliminates TBK1-mediated suppression of MCPyV replication during early infection of human dermal fibroblasts (HDFs). These findings provide mechanistic insight into how ALTO promotes viral persistence and immune evasion. More broadly, they highlight the functional importance of intrinsically disordered regions in modulating host-virus interactions and suggest that MCPyV latency is actively maintained through a finely tuned balance of pro- and anti-viral signaling. Targeting domains such as LIT may offer new strategies for regulating TBK1 activity or disrupting viral persistence. ImportanceMerkel cell polyomavirus causes lifelong, latent infections in the skin of most people. When this latency is perturbed, the virus can give rise to Merkel Cell Carcinoma, an aggressive and difficult-to-treat skin cancer. Efforts to prevent this cancer depend on understanding what controls viral latency and persistence. We previously reported that MCPyV stimulates the hosts STING-TBK1 signaling axis to limit its own replication. In this work, we identify and characterize a short amino acid motif within the ALTO proteins intrinsically disordered region that is required for this immune-stimulating activity. This region appears to be critical for helping the virus maintain latency by fine-tuning the hosts response. Our findings provide new insight into MCPyVs latency mechanism and may help guide future approaches to prevent or treat Merkel cell carcinoma by targeting viral or cellular factors involved in long-term infection.

microbiology↗

bioRxiv2024

Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative-feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy. Author summaryMerkel cell polyomavirus (MCPyV) is a small DNA virus responsible for the majority cases of Merkel Cell Carcinoma (MCC), a rare yet highly aggressive form of cancer. While MCPyV latently infects a vast majority of individuals, the mechanisms governing its control, persistence, and oncogenic triggers remain obscure. Our research reveals that the MCPyV-derived Alternative Large Tumor Open Reading Frame (ALTO) protein primes and activates the cGAS-STING- TBK1 innate immune pathway within cells. Such activation elicits an antiviral response, effectively curbing MCPyV replication. This phenomenon illustrates the viruss cunning strategy to exploit cellular mechanisms, ensuring low viral presence while facilitating long-term infection. Consequently, our study sheds light on a novel tactic utilized by MCPyV to maintain a persistent infection in its host.

microbiology↗