The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation

Abstract

The identification of several families of innate pattern recognition receptors has greatly enhanced our understanding of the host innate immune response against a variety of pathogens. One such family of innate receptors is the nucleotide-binding domain and leucine rich repeat containing receptors (NLRs). NOD2 has been characterized as a cytosolic sensor of bacteria peptidoglycan (PGN). For almost 10 years, NOD2 was assigned with the function of mediating the RICK- and nuclear factor-κB induced proinflammatory response triggered by PGN. Recent studies have extended the biological activity of NOD2 to include the induction of autophagy and antiviral responses, as well as mediating direct T cell activation. Here, we highlight and discuss these new findings in the context of immune activation and pathogen detection.

Figure 1

NOD2 activates the autophagy pathway. Bacteria is engaged by NOD2 and functions to recruit ATG16L1 to the plasma membrane. The interaction of NOD2 and ATG16L1 leads to the formation of autophagosome. The fusion of the autophagosome with the lysosome promotes the processing/loading of bacterial peptide onto MHC II molecule. The peptide-MHC II complex leads to appropriate T cell activation and bacteria clearance. Consistent with the role of NOD2 induction of autophagy is the finding that NOD2 mutation fails to induce autophagy.

Figure 2

‘Classic’ versus ‘alternative’ pathways activated by NOD2. The classical pathway is identified by the engagement of NOD2 by MDP, which involves the kinase, RICK. As a consequence this leads to the activation of NF-κB, leading to inflammatory gene expression. The ‘alternative’ pathway involves ssRNA virus, where ssRNA interacts with NOD2, which binds to MAVS present on the mitochondria; leading to IRF3 activation and IFN gene expression that is RICK-independent. NLRX1 is an NLR family member that inhibits MAVS at the mitochondrial membrane.

Figure 3

NOD2 functions in T cells and macrophages (Mθ). TCR and CD28 signaling triggers the activation of NOD2. In T cells, NOD2 interacts with NF-kB inducing kinase (NIK) and c-Rel to form a complex that promotes c-Rel nuclear accumulation. The molecular mechanisms that link TCR, CD28 and NOD2 are unknown. Similarly, it is unclear whether NOD2 function in T cells is exclusive to CD28 or is shared by other costimulatory molecules.