Pleiotropic Properties of Rotavirus Nonstructural Protein 4 (NSP4) and Their Effects on Viral Replication and Pathogenesis

Rotavirus (RV), the causative agent of infantile diarrhea in a wide range of hosts, encodes a multifunctional nonstructural protein, NSP4. Interactions of NSP4 with both host factors and other viral proteins are critical for viral replication, morphogenesis, and pathogenesis. This review focuses on the strategies used by intracellular NSP4 (iNSP4) and extracellular NSP4 (eNSP4) to induce diarrhea, to modulate intracellular calcium homeostasis, apoptosis, and tight junction integrity, to regulate viral transcription, replication, and morphogenesis; as well as exploit cellular processes, such as protein trafficking and autophagy, required for RV biology. The molecular mechanisms underpinning the numerous roles for NSP4 are discussed with particular emphasis towards delineating both the functional domains and the structural forms of NSP4 required for its many activities. Defining the multiple functions of NSP4 is important to fully understand rotavirus replication and pathogenesis and will possibly lead to new approaches to prevent or treat disease.