Dual Immunomodulatory Roles of MARCKS in Proinflammatory and Type I Interferon Signaling in Macrophages 2306298

Introduction Lipopolysaccharide (LPS) signaling plays a critical role in innate immune responses and inflammation. Myristoylated alanine-rich C-kinase substrate (MARCKS) has been implicated in various signaling pathways; however, its immunomodulatory mechanisms remain unclear. In this study, we used proteogenomic analysis to investigate the function of MARCKS in the LPS response. Unexpectedly, our results revealed that MARCKS acts as both a positive and negative regulator of LPS signaling, suggesting a reciprocal role of MARCKS. This dual role challenges the current understanding of MARCKS function. In macrophages, loss of MARCKS resulted in reduced inflammation, marked by decreased TNF-induced amplification and attenuated activation of NF-κB and MAPK pathways. In contrast, MARCKS deficiency enhanced interferon signaling, with elevated IFN-β production and upregulation of interferon-stimulated genes (ISGs) via the JAK-STAT pathway. These findings reveal a previously unrecognized dual function of MARCKS in modulating both inflammatory and interferon responses, with implications for targeting immune dysregulation in disease Methods Results Conclusion Funding Source This research was supported by the Intramural Research Program of NIAID, NIH.