Znrf4, also known as Nixin, is an E3 ubiquitin ligase with significant roles in biological processes. It is involved in the regulation of endoplasmic reticulum (ER) homeostasis and innate immune responses, which are crucial for maintaining normal cellular function and host immunity [2,1].

In innate immunity, Znrf4 negatively regulates NOD2 signalling. It induces K48-linked ubiquitination of RIP2, a NOD2 adaptor, promoting its degradation. Znrf4 knockdown monocytes show sustained NF-κB activation, and Znrf4 knockdown mice have reduced NOD2-induced tolerance but more effective control of Listeria monocytogenes infection. These results from loss-of-function experiments in mice demonstrate that Znrf4-mediated RIP2 degradation is a negative regulatory mechanism of NOD2-induced NF-κB, cytokine and anti-bacterial responses in vivo [1].

In conclusion, Znrf4 is essential for regulating ER homeostasis and innate immune responses. The study of Znrf4 knockdown mouse models has revealed its significance in modulating NOD2-related immune responses, which may contribute to understanding the mechanisms of immune-related diseases and developing potential therapeutic strategies for controlling infections and inflammatory disorders.

References:

1. Bist, Pradeep, Cheong, Wan Shoo, Ng, Aylwin, Xavier, Ramnik J, Sukumaran, Bindu. 2017. E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. In Nature communications, 8, 15865. doi:10.1038/ncomms15865. https://pubmed.ncbi.nlm.nih.gov/28656966/

2. Neutzner, Albert, Neutzner, Melanie, Benischke, Anne-Sophie, Youle, Richard J, Karbowski, Mariusz. 2011. A systematic search for endoplasmic reticulum (ER) membrane-associated RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin stability and ER homeostasis. In The Journal of biological chemistry, 286, 8633-8643. doi:10.1074/jbc.M110.197459. https://pubmed.ncbi.nlm.nih.gov/21205830/