SHARPIN, the SHANK-associated RH domain-interacting protein, is a multifunctional protein. It can form the linear ubiquitin chain assembly complex (LUBAC) with HOIL-1L and HOIP, producing a linear ubiquitin chain connected N-terminal Met1, which is crucial for NF-κB signaling, inflammation, embryogenesis, and apoptosis. It is also involved in numerous physiological functions and associated with many diseases [2,3].

In mice, loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death [4]. In humans, SHARPIN deficiency causes autoinflammatory symptoms, with fibroblasts and B cells showing attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals have a reduction in secondary lymphoid germinal center B cell development [4]. In cancer, SHARPIN promotes the proliferation of cholangiocarcinoma cells and inhibits ferroptosis via the p53/SLC7A11/GPX4 signaling pathway [1]. It also promotes breast cancer progression, controlling important carcinogenic pathways such as p53 and ERα [5]. In melanoma, it promotes metastasis through the Rap1 signaling pathway [6], and in colorectal cancer, it promotes tumor growth by potentially inhibiting p53 expression [7].

In conclusion, SHARPIN is essential for NF-κB signaling, inflammation, and apoptosis regulation. Studies on SHARPIN-deficient models, especially in mice, have revealed its key role in skin-related inflammation, autoinflammatory diseases, and cancer development. Understanding SHARPIN's functions provides potential therapeutic targets for these disease areas.

References:

1. Zeng, Chong, Lin, Jie, Zhang, Ketao, Wang, Weidong, Yao, Jie. 2022. SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling. In Cancer science, 113, 3766-3775. doi:10.1111/cas.15531. https://pubmed.ncbi.nlm.nih.gov/35968603/

2. Krishnan, Dhanya, Menon, Ramsekhar N, Gopala, Srinivas. 2021. SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer's Disease? In Cellular and molecular neurobiology, 42, 1267-1281. doi:10.1007/s10571-020-01023-w. https://pubmed.ncbi.nlm.nih.gov/33400084/

3. Yu, Beiming, Wang, Feng, Wang, Yanfeng. 2022. Advances in the Structural and Physiological Functions of SHARPIN. In Frontiers in immunology, 13, 858505. doi:10.3389/fimmu.2022.858505. https://pubmed.ncbi.nlm.nih.gov/35547743/

4. Oda, Hirotsugu, Manthiram, Kalpana, Chavan, Pallavi Pimpale, Aksentijevich, Ivona, Kastner, Daniel L. 2024. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. In Nature immunology, 25, 764-777. doi:10.1038/s41590-024-01817-w. https://pubmed.ncbi.nlm.nih.gov/38609546/

5. Tian, Zelin, Tang, Jianing, Yang, Qian, Zhu, Jian, Wu, Gaosong. 2019. Atypical ubiquitin-binding protein SHARPIN promotes breast cancer progression. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 119, 109414. doi:10.1016/j.biopha.2019.109414. https://pubmed.ncbi.nlm.nih.gov/31518875/

6. Zhou, Sitong, Liang, Yanhua, Zhang, Xi, Ouyang, Wen, Xu, Huaiyuan. 2019. SHARPIN Promotes Melanoma Progression via Rap1 Signaling Pathway. In The Journal of investigative dermatology, 140, 395-403.e6. doi:10.1016/j.jid.2019.07.696. https://pubmed.ncbi.nlm.nih.gov/31401046/

7. Nakano, Yusuke, Masuda, Takaaki, Sakamoto, Takeharu, Doki, Yuichiro, Mimori, Koshi. 2024. SHARPIN is a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression. In International journal of oncology, 65, . doi:10.3892/ijo.2024.5701. https://pubmed.ncbi.nlm.nih.gov/39450547/