Host protein cleavage by Dengue and Zika virus NS3 proteases: from substrate identification to potential biological consequences.

Dengue virus (DENV) and Zika virus (ZIKV) are medically important orthoflaviviruses that utilize the multifunctional NS3 protease, in complex with its cofactor NS2B, for viral replication and host modulation. Here, we summarize current knowledge of host proteins targeted by NS3 proteases and discuss recent advances in proteomic and computational approaches for identifying these substrates. We further discuss evidence showing that NS2B3-mediated cleavage alters innate immune signaling, autophagy, protein translation, and cytoskeletal dynamics. In addition, we compare the host substrate specificities of DENV and ZIKV proteases, emphasizing both shared mechanisms and virus-specific differences that may contribute to their distinct disease manifestations. A deeper understanding of NS3-mediated host protein cleavage will provide critical insights into orthoflavivirus biology and further establish NS3 as a promising target for antiviral intervention.