Rhomboid domain-containing protein 3 is a negative regulator of TLR3-triggered natural killer cell activation

Abstract

Rhomboid domain-containing protein 3 (Rhbdd3), which belongs to a family of proteins with rhomboid domain, is widely expressed in immune cells; however, the roles of the Rhbdd members, including Rhbdd3, in immunity remain unknown. Natural killer (NK) cells are critical for host immune defense and also can mediate inflammatory diseases such as hepatitis. Although much is known about how NK cells are activated, the detailed mechanisms for negative regulation of NK cell activation remain to be fully understood. Using Rhbdd3-deficient mice, we reveal that Rhbdd3, selectively up-regulated in NK cells upon Toll-like receptor 3 (TLR3) stimulation, negatively regulates TLR3-mediated NK cell activation in a feedback manner. Rhbdd3 inhibits TLR3-triggered IFN-γ and granzyme B expression of NK cells in cell-cell contact dependence of accessory cells such as dendritic cells and Kupffer cells. Rhbdd3 interacts with DNAX activation protein of 12 kDa and promotes its degradation, inhibiting MAPK activation in TLR3-triggered NK cells. Furthermore, Rhbdd3 plays a critical role in attenuating TLR3-triggered acute inflammation by controlling NK cell activation and accumulation in liver and disrupting NK cellKupffer cell interaction. Therefore, Rhbdd3 is a feedback inhibitor of TLR3-triggered NK cell activation. Our study outlines a mechanism for the negative regulation of NK cell activation and also provides clues for the function of the rhomboid proteins in immunity.poly(I:C) | innate immunity | immune regulation

Cellular and molecular regulation of innate inflammatory responses

“…Mechanistically, Rhbdd3 localizes in early endosomes in DCs and interacts with K27-linked ubiquitination of NF-κB essential modifier (NEMO) and subsequently recruits A20 to facilitate A20-mediated K63-linked deubiquitination of NEMO. 72,73 By contrast, iRhom2, a novel noncatalytic relative of rhomboid proteins, facilitates LPS and Listeria-induced TNF production by promoting the TNF convertase (TACE) maturation and trafficking, 74,75 and also enhances innate immunity to DNA viruses by mediating STING trafficking and stability. 76 The differential regulation of innate immunity by Rhomboid family members awaits further investigation, and is likely to be related with their different subcellular localization that may provide specific biochemical and physical environment for specific signaling modifications.…”

Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

“…Moreover, Rhbdd3 expression is also lower in the colonic mucosal tissues of patients with ulcerative colitis and Crohn's disease, as well as in the ileum tissues of patients with Crohn's disease. In addition, Rhbdd3 −/− mice are prone to developing autoimmune disorders . All of this evidence taken together suggests a link between Rhbdd3 and autoimmune or chronic inflammatory diseases.…”

“…Rhbdd3 is also found to be highly induced by LPS in bone marrow‐derived DCs . Interestingly, another study shows that Rhbdd3 is selectively up‐regulated in natural killer (NK) cells treated with poly(I:C), a ligand for TLR3 . Mechanistically, Rhbdd3 interacts with and promotes the degradation of DAP12, which is a key intracellular accessory adaptor for several activating receptors on NK cells, leading to the inhibition of TLR3‐mediated NK cell activation .…”

“…Mechanistically, Rhbdd3 interacts with and promotes the degradation of DAP12, which is a key intracellular accessory adaptor for several activating receptors on NK cells, leading to the inhibition of TLR3-mediated NK cell activation [29]. It has also been reporetd that Rhbdd3 attenuates TLR3-triggered acute inflammation by controlling NK cell activation and accumulation in the livers and disrupting the NK-Kupffer cell interaction [29]. Collectively, these studies suggest that different rhomboid-like pseudoproteases play positive or negative feedback regulatory roles in inflammatory responses triggered by different stimuli.…”

Innate recognition of microbial-derived signals in immunity and inflammation

“…Accumulating studies have suggested that lack of positive adaptors of PRRs protects host from microbial pathogen challenge, while negative regulators deficiency can cause excessive inflammatory immune responses and increased susceptibility to endotoxic shock after microbial components stimulation . Recently, it has shown that Rhbdd3 plays a critical role in attenuating TLR3-triggered acute inflammation by controlling NK cell activation in liver, and suppresses the production of IL-6 in dendritic cells via K27-linked ubiquitination of the regulator NEMO and was involved in the control of IBD (Liu et al, 2013a;Liu et al, 2014). The autophagy protein ATG16L1 has been identified to suppress Nod-driven inflammatory responses and contribute to the chronic inflammation associated with Crohn's disease (Sorbara et al, 2013).…”