Nsfl1c, also known as p47, is a co-factor protein that plays diverse roles in multiple biological pathways. It is associated with the function of valosin-containing protein (VCP/p97), participating in processes like intracellular membrane traffic regulation, and has potential links to autophagy and protein-protein interactions [3,7,8].

In BRCA2-mutated prostate cancer models, loss of NSFL1C suppressed spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation [1]. In HER2+ breast cancer, p47 (encoded by Nsfl1c) was identified as a suppressor of metastasis through regulating NEMO trafficking and autophagy flux. p47 ablation specifically increased metastasis without promoting primary mammary tumor growth [4]. In studies related to neurodegenerative tauopathies, reduction of NSFL1C decreased tau seeding, indicating its role in the early tau seed amplification process regulated by VCP [2,5,6].

In conclusion, NSFL1C is a crucial factor involved in cancer-related processes such as metastasis and survival adaptation of cancer cells, as well as in neurodegenerative disease-associated tau seeding. Gene-knockout or knockdown models in these contexts have been instrumental in uncovering its functions, providing insights into potential therapeutic targets for prostate and breast cancers, and neurodegenerative tauopathies.

References:

1. Wang, Jian, Chen, Yuke, Li, Shiwei, Wang, Weibin, Wang, Jiadong. 2024. PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation. In The Journal of clinical investigation, 134, . doi:10.1172/JCI172137. https://pubmed.ncbi.nlm.nih.gov/37934606/

2. Batra, Sushobhna, Vaquer-Alicea, Jaime Iii, Valdez, Clarissa, White, Charles L, Diamond, Marc I. 2024. VCP regulates early tau seed amplification via specific cofactors. In Research square, , . doi:10.21203/rs.3.rs-4307848/v1. https://pubmed.ncbi.nlm.nih.gov/38826306/

3. Wang, Kent Z Q, Steer, Erin, Otero, P Anthony, Hsueh, Yi-Ping, Chu, Charleen T. 2018. PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons. In eNeuro, 5, . doi:10.1523/ENEURO.0466-18.2018. https://pubmed.ncbi.nlm.nih.gov/30783609/

4. Hao, Mingang, Lu, Peixin, Sotropa, Sarah, Yeo, Syn Kok, Guan, Jun-Lin. 2024. In vivo CRISPR knockout screen identifies p47 as a suppressor of HER2+ breast cancer metastasis by regulating NEMO trafficking and autophagy flux. In Cell reports, 43, 113780. doi:10.1016/j.celrep.2024.113780. https://pubmed.ncbi.nlm.nih.gov/38363674/

5. Batra, Sushobhna, Vaquer-Alicea, Jaime, Valdez, Clarissa, White, Charles L, Diamond, Marc I. 2025. VCP regulates early tau seed amplification via specific cofactors. In Molecular neurodegeneration, 20, 2. doi:10.1186/s13024-024-00783-z. https://pubmed.ncbi.nlm.nih.gov/39773263/

6. Batra, Sushobhna, Vaquer-Alicea, Jaime, Manon, Victor A, White, Charles L, Diamond, Marc I. 2023. VCP increases or decreases tau seeding using specific cofactors. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.08.30.555637. https://pubmed.ncbi.nlm.nih.gov/37693404/

7. Jiang, Ziwen, Kuo, Yu-Hsuan, Zhong, Mengqi, Wang, Yanzhuang, Arkin, Michelle R. 2022. Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein-Protein Interactions. In Journal of the American Chemical Society, 144, 13218-13225. doi:10.1021/jacs.2c03665. https://pubmed.ncbi.nlm.nih.gov/35819848/

8. Hindle, Allyson G, Grabek, Katharine R, Epperson, L Elaine, Karimpour-Fard, Anis, Martin, Sandra L. 2014. Metabolic changes associated with the long winter fast dominate the liver proteome in 13-lined ground squirrels. In Physiological genomics, 46, 348-61. doi:10.1152/physiolgenomics.00190.2013. https://pubmed.ncbi.nlm.nih.gov/24642758/