Bri3, also known as ITM2C, is a member of the BRI gene family. It has been implicated in multiple biological processes. In the central nervous system, it may function as a molecular chaperone through its BRICHOS domain, with effects against amyloid formation and non-fibrillar protein aggregation [1,6]. It is also involved in TNF-induced cell death, as overexpression of BRI3 induced apoptosis in L929 cells, and disruption of its expression promoted resistance to TNF-induced cell death [2]. Additionally, BRI3 associates with SCG10, blocking SCG10-induced microtubule disassembly, stabilizing the microtubule network, and attenuating NGF-induced neurite outgrowth in PC12 cells [3]. It also serves as an endogenous negative regulator of Abeta production by interacting with amyloid precursor protein (APP) and inhibiting APP processing [4]. BRI3 is a phosphoprotein that binds to protein phosphatase 1 (PP1), and its phosphorylation may have functional implications [5].

Functional studies have shown that the recombinant Bri3 BRICHOS domain forms more and larger oligomers, more efficiently prevents non-fibrillar protein aggregation, but less efficiently reduces Aβ42 fibril formation compared to Bri2 BRICHOS, suggesting overlapping molecular mechanisms but potentially different physiological functions due to different tissue expression and processing [1]. In neurons, Bri3 deposits are dispersed on AD plaques, and its immunoreactivity is decreased in AD brain homogenates. Both Bri2 and Bri3 BRICHOS domains interact with Aβ40 and Aβ42 and reduce Aβ42 amyloid fibril formation in vitro, with Bri3 BRICHOS being less efficient [6]. Knockdown of BRI3 in neuronal cells increases Aβ production, as BRI3 is a physiological inhibitor of APP processing and Aβ oligomerization [7]. In rat hippocampal neurons, knockdown of BRI3 by siRNA abrogated cell survival and induced cell apoptosis, indicating its role in regulating cell death [8].

In conclusion, Bri3 plays crucial roles in various biological processes such as amyloid regulation, cell death, and neuronal differentiation. Studies on Bri3, including those using knockdown models, have provided insights into its functions in diseases like Alzheimer's disease and TNF-related cell death conditions. These findings contribute to understanding the underlying mechanisms of these diseases and may potentially lead to new therapeutic strategies.

References:

1. Poska, Helen, Leppert, Axel, Tigro, Helene, Chen, Gefei, Johansson, Jan. 2020. Recombinant Bri3 BRICHOS domain is a molecular chaperone with effect against amyloid formation and non-fibrillar protein aggregation. In Scientific reports, 10, 9817. doi:10.1038/s41598-020-66718-y. https://pubmed.ncbi.nlm.nih.gov/32555390/

2. Wu, Haoquan, Liu, Gang, Li, Changben, Zhao, Shouyuan. . bri3, a novel gene, participates in tumor necrosis factor-alpha-induced cell death. In Biochemical and biophysical research communications, 311, 518-24. doi:. https://pubmed.ncbi.nlm.nih.gov/14592447/

3. Gong, Yanhua, Wu, Jing, Qiang, Hua, Peng, Xiaozhong, Yuan, Jiangang. . BRI3 associates with SCG10 and attenuates NGF-induced neurite outgrowth in PC12 cells. In BMB reports, 41, 287-93. doi:. https://pubmed.ncbi.nlm.nih.gov/18452648/

4. Matsuda, Shuji, Matsuda, Yukiko, D'Adamio, Luciano. 2009. BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2. In The Journal of biological chemistry, 284, 15815-25. doi:10.1074/jbc.M109.006403. https://pubmed.ncbi.nlm.nih.gov/19366692/

5. Martins, Filipa, Rebelo, Sandra, Santos, Mariana, da Cruz e Silva, Edgar F, da Cruz e Silva, Odete A B. 2015. BRI2 and BRI3 are functionally distinct phosphoproteins. In Cellular signalling, 28, 130-44. doi:10.1016/j.cellsig.2015.10.012. https://pubmed.ncbi.nlm.nih.gov/26515131/

6. Dolfe, Lisa, Tambaro, Simone, Tigro, Helene, Johansson, Jan, Presto, Jenny. 2018. The Bri2 and Bri3 BRICHOS Domains Interact Differently with Aβ42 and Alzheimer Amyloid Plaques. In Journal of Alzheimer's disease reports, 2, 27-39. doi:10.3233/ADR-170051. https://pubmed.ncbi.nlm.nih.gov/30480246/

7. Yasukawa, Takashi, Tsutsui, Aya, Tomomori-Sato, Chieri, Conaway, Joan W, Aso, Teijiro. . NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation. In Cell reports, 30, 3478-3491.e6. doi:10.1016/j.celrep.2020.02.059. https://pubmed.ncbi.nlm.nih.gov/32160551/

8. Yang, Liu, Xiong, Yin, Hu, Xian-Feng, Du, Yan-Hua. 2015. MicroRNA-323 regulates ischemia/reperfusion injury-induced neuronal cell death by targeting BRI3. In International journal of clinical and experimental pathology, 8, 10725-33. doi:. https://pubmed.ncbi.nlm.nih.gov/26617783/