Tm9sf1, also known as MP70 and HMP70, is a member of the transmembrane 9 superfamily proteins. It has a long N-terminal extracellular region and nine transmembrane domains. While its exact physiological functions are still being explored, it is involved in processes such as autophagy and is associated with various diseases, indicating its importance in biological systems. Genetic models, like knockout mouse models, have been crucial in uncovering its functions [2,3,4,5].

In knockout mouse models, Tm9sf1-/-mouse rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) models produced fewer autoantibodies and showed reduced disease severity. This indicates that Tm9sf1 modulates mTOR-dependent autophagy to regulate B cell differentiation into antibody-secreting plasma cells, and its expression level in peripheral blood mononuclear cells (PBMCs) can be an indicator of disease activity in RA and SLE patients [1]. In a mouse model of acute lung injury, Tm9sf1 knockout significantly alleviated LPS-induced injury, with higher survival rate, improved pulmonary vascular permeability, decreased inflammatory cell infiltration, and downregulated inflammatory cytokines. Tm9sf1 was shown to be a negative regulator of autophagy in this model [3]. In colorectal cancer, Tm9sf1 knockout significantly increased tumor numbers and size, as well as enhanced tumor invasion, suggesting it suppresses metastasis via selective autophagic degradation of Vimentin [4].

In conclusion, Tm9sf1 is involved in autophagy-related regulatory mechanisms and plays a role in multiple disease conditions such as autoimmune diseases, acute lung injury, and colorectal cancer. The use of Tm9sf1 knockout mouse models has been instrumental in revealing its functions in these diseases, providing potential targets for treatment and a better understanding of the underlying biological processes.

References:

1. Xiao, Juan, Zhao, Zhenwang, Zhou, Fengqiao, Zhang, Anbing, Wang, Ke. 2024. TM9SF1 expression correlates with autoimmune disease activity and regulates antibody production through mTOR-dependent autophagy. In BMC medicine, 22, 502. doi:10.1186/s12916-024-03729-w. https://pubmed.ncbi.nlm.nih.gov/39482663/

2. Wei, Long, Wang, Shi-Shuo, Huang, Zhi-Guang, Li, Sheng-Hua, Chen, Gang. . TM9SF1 promotes bladder cancer cell growth and infiltration. In World journal of clinical oncology, 15, 302-316. doi:10.5306/wjco.v15.i2.302. https://pubmed.ncbi.nlm.nih.gov/38455139/

3. Xiao, Juan, Shen, Xiaofang, Chen, Huabo, Zhai, Lihong, Mao, Chun. 2022. TM9SF1 knockdown decreases inflammation by enhancing autophagy in a mouse model of acute lung injury. In Heliyon, 8, e12092. doi:10.1016/j.heliyon.2022.e12092. https://pubmed.ncbi.nlm.nih.gov/36561687/

4. Wang, Huifen, Hu, Jia, Wang, Di, Li, Ang, Liu, Zhibo. 2025. TM9SF1 inhibits colorectal cancer metastasis by targeting Vimentin for Tollip-mediated selective autophagic degradation. In Cell death and differentiation, , . doi:10.1038/s41418-025-01498-4. https://pubmed.ncbi.nlm.nih.gov/40175707/

5. Azuma, Kotaro, Ikeda, Kazuhiro, Shiba, Sachiko, Tanaka, Shinya, Inoue, Satoshi. 2024. EBAG9-deficient mice display decreased bone mineral density with suppressed autophagy. In iScience, 27, 108871. doi:10.1016/j.isci.2024.108871. https://pubmed.ncbi.nlm.nih.gov/38313054/