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 NOD-like receptors (NLRs). NOD2, a member of the NLRs, was characterized as a cytosolic sensor of bacteria peptidoglycan (PGN). For almost 10 years, NOD2 was assigned with the function of mediating the RICK- and NF-κB induced pro-inflammatory 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.

Autophagy in physiological and pathological processes – selected aspects

“…Studies on mammalian cells revealed that Nod1 and Nod2 were able to interact with Atg16L1 and, additionally, Nod2 induced this process in dendritic cells intensifying the antigen presentation by MHC class II. Further observations showed that interactions with NLRs and autophagy machinery leads to augmented control of the bacterial infections (Shaw et al 2011). Activation of autophagy can be mediated also by RLRs (Rig-like receptors) (Deretic 2011), while recent investigations revealed a new group of innate immunity receptors -SLRs -sequestasome (p62/SQSTM1) -like receptors, which are mainly responsible for recognition of endogenous bacteria and triggering them into autophagic pathway (Deretic 2011).…”

Molecular interactions of autophagy with the immune system and cancer

“…Moreover, they participate in regulating autophagy by interacting with ATG16L1, which mediates autophagosome formation, at the cell membrane [11,21]. NOD2 also recognizes invasive bacteria, thereby triggering autophagy and leading to NOD2-mediated host defenses [13]. Both NOD1 and NOD2 are thought to engage not only in innate and adaptive immune responses but also in the interaction between autophagy and cancer [11,22].…”

Crohn’s Disease: a Role of Gut Microbiota and Nod2 Gene Polymorphisms in Disease Pathogenesis

“…During allogeneic bone marrow transplantation lack of Nod2 regulatory function in dendritic cells leads to enhanced proliferation and activation of allogeneic donor T cells presumably under the influence of endogenous TLR ligands, which results in target organ damage in graft versus host disease (GvHD) (69).…”

“…C-Rel mediated IL-2 production positively regulates T cell activation and differentiation and plays a crucial role in T cell priming for IFN-γ production (70). Studies have demonstrated that c-Rel that is activated in response to TCR and CD28 triggering binds to regulatory element present in the forkhead box P3 (Foxp3) promoter region to facilitate Foxp3 expression and to promote T-regulatory (Treg) cell differentiation an thus may contribute to dysregulated immune response in Nod2-deficient host (69).…”