This review discusses the structural and mechanistic basis of innate immune antagonism by two direct effectors, the Rotavirus NSP1 and VP3 proteins. It starts with a nice overview of Rotavirus biology then goes on to describe how the structural and mechanistic properties of NSP1 and VP3 allow these proteins to directly antagonize host innate immune responses.
NSP1 is a putative E3 ubiquitin ligase that mediates the degradation of a wide range of cellular targets, including those that function as innate immune sensors (RIG-I), signaling intermediates (TRAF2, MAVS, and β-TrCP), transcription factors (IRFs), and mediators of host survival pathways (PI3K and p53). In many respects, VP3 is like two proteins in one: it caps viral transcripts as they emerge from RV DLPs, which likely prevents activation of host RNA sensors, and it directly antagonizes the dsRNA-responsive OAS/RNase L pathway by cleaving the signaling molecule 2-5A. VP3 may also function in two distinct regions of the cell during infection: within a viral particle as the capping enzyme and perhaps also within the cytoplasm as a direct innate immune antagonist.
The varied functions of NSP1 and VP3 highlight the diversity and importance of cellular innate immune defenses to RNA viruses and reflect the compactness of a viral genome.
Silencing the alarms: Innate immune antagonism by rotavirus NSP1 and VP3. Virology. 24 Feb 2015 doi: 10.1016/j.virol.2015.01.006
TThe innate immune response involves a broad array of pathogen sensors that stimulate the production of interferons (IFNs) to induce an antiviral state. Rotavirus, a significant cause of childhood gastroenteritis and a member of the Reoviridae family of segmented, double-stranded RNA viruses, encodes at least two direct antagonists of host innate immunity: NSP1 and VP3. NSP1, a putative E3 ubiquitin ligase, mediates the degradation of cellular factors involved in both IFN induction and downstream signaling. VP3, the viral capping enzyme, utilizes a 2H-phosphodiesterase domain to prevent activation of the cellular oligoadenylate synthase (OAS)/RNase L pathway. Computational, molecular, and biochemical studies have provided key insights into the structural and mechanistic basis of innate immune antagonism by NSP1 and VP3 of group A rotaviruses (RVA). Future studies with non-RVA isolates will be essential to understand how other rotavirus species evade host innate immune responses.