Spsb2, the SPRY domain-and SOCS box-containing protein 2, belongs to the SPSB family. It functions as an adaptor protein that recruits target proteins via its SPRY domain and forms E3 ubiquitin ligase complexes through the SOCS box. Spsb2 is involved in regulating the host's response to infection and is associated with the ubiquitination-mediated degradation pathway [1,2,3,4,5,6].

In HCV infection, HCV-infected cells show significantly upregulated mRNA and protein levels of Spsb2. Exogenous expression of Spsb2 in hepatoma cells decreases HCV RNA and protein levels in a SOCS-box-dependent manner, while knockdown of endogenous Spsb2 increases them. Spsb2 interacts with HCV structural protein E1 and non-structural protein NS5A, induces NS5A ubiquitination, and mediates its degradation, thus significantly inhibiting HCV replication [1]. Also, Spsb2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Spsb2-deficient macrophages show prolonged iNOS expression, increased NO production, and enhanced killing of Leishmania major parasites [6]. MDM2, an E3 ubiquitin ligase, triggers the ubiquitination and degradation of Spsb2 to stabilize iNOS and increase NO production, which activates HIF-1α for glycolytic and pro-inflammatory programs in M1 macrophages [3].

In summary, Spsb2 plays a crucial role in host-pathogen interactions, particularly in regulating the replication of HCV and the production of nitric oxide via iNOS degradation. The findings from studies on Spsb2, including knockdown and deficiency models, help to understand its role in viral infection and innate immune response-related diseases, potentially providing new insights for the treatment of HCV-related diseases and infections where modulation of iNOS-NO pathway is beneficial [1,3,6].

References:

1. Wang, Mingzhen, Wang, Yu, Liu, Yuehong, Zheng, Congyi, Shen, Chao. 2019. SPSB2 inhibits hepatitis C virus replication by targeting NS5A for ubiquitination and degradation. In PloS one, 14, e0219989. doi:10.1371/journal.pone.0219989. https://pubmed.ncbi.nlm.nih.gov/31344133/

2. Yap, Beow Keat, Leung, Eleanor W W, Yagi, Hiromasa, Thompson, Philip E, Norton, Raymond S. 2014. A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent. In Journal of medicinal chemistry, 57, 7006-15. doi:10.1021/jm500596j. https://pubmed.ncbi.nlm.nih.gov/25068993/

3. Wu, Kelvin Ka-Lok, Xu, Xiaofan, Wu, Manyin, Hui, Hannah Xiaoyan, Cheng, Kenneth King-Yip. 2024. MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice. In Nature communications, 15, 8624. doi:10.1038/s41467-024-53006-w. https://pubmed.ncbi.nlm.nih.gov/39366973/

4. Li, Kefa, You, Tingting, Zhao, Panqi, Guan, Xueyan, Kuang, Zhihe. 2021. Structural basis for the regulation of inducible nitric oxide synthase by the SPRY domain-containing SOCS box protein SPSB2, an E3 ubiquitin ligase. In Nitric oxide : biology and chemistry, 113-114, 1-6. doi:10.1016/j.niox.2021.04.004. https://pubmed.ncbi.nlm.nih.gov/33862200/

5. You, Tingting, Wang, Yuhui, Li, Kefa, Su, Xunchen, Kuang, Zhihe. 2017. Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction. In Biochemical and biophysical research communications, 489, 346-352. doi:10.1016/j.bbrc.2017.05.122. https://pubmed.ncbi.nlm.nih.gov/28549582/

6. Kuang, Zhihe, Lewis, Rowena S, Curtis, Joan M, Norton, Raymond S, Nicholson, Sandra E. 2010. The SPRY domain-containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation. In The Journal of cell biology, 190, 129-41. doi:10.1083/jcb.200912087. https://pubmed.ncbi.nlm.nih.gov/20603330/