CHMP5, also known as Charged multivesicular body protein 5, is a member of the endosomal-sorting complex required for transport (ESCRT) [4,5]. It has a key role in multivesicular body biogenesis and down-regulation of signaling pathways through receptor degradation [6]. CHMP5 is involved in regulating late endosome function, and its activity is associated with the NF-κB signaling pathway, which is crucial in various biological processes [3].

In an OA mouse model constructed by destabilization of the medial meniscus, downregulated CHMP5 was identified in OA patient cartilages. Overexpression of CHMP5 repressed chondrocyte apoptosis and extracellular matrix degradation, while silencing CHMP5 exacerbated these processes, suggesting its protective role in OA via the NF-κB pathway [3]. Conditional deletion of CHMP5 in osteoclasts led to increased bone resorption by osteoclasts and exuberant bone formation by osteoblasts, resembling Paget's disease of bone. CHMP5-deficient osteoclasts showed increased RANKL-induced NF-κB activation and osteoclast differentiation [3]. In T-ALL models, loss of CHMP5 diminished BRD4 occupancy at enhancers and super-enhancers, impaired RNA polymerase II pause release, and downregulated key T-ALL genes, indicating its role in promoting T-ALL [2].

In conclusion, CHMP5 plays essential roles in multiple biological processes and disease conditions. Mouse models, such as KO or CKO models, have revealed its significance in OA, bone remodeling, and T-ALL. Understanding CHMP5's functions provides potential therapeutic targets for these diseases [1,2,3].

References:

1. Gao, Weilu, Liu, Rui, Huang, Keke, Yin, Li, Yin, Zongsheng S. 2024. CHMP5 attenuates osteoarthritis via inhibiting chondrocyte apoptosis and extracellular matrix degradation: involvement of NF-κB pathway. In Molecular medicine (Cambridge, Mass.), 30, 55. doi:10.1186/s10020-024-00819-6. https://pubmed.ncbi.nlm.nih.gov/38664616/

2. Umphred-Wilson, Katharine, Ratnayake, Shashikala, Tang, Qianzi, Singer, Dinah S, Adoro, Stanley. 2024. The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.01.29.577409. https://pubmed.ncbi.nlm.nih.gov/38352301/

3. Greenblatt, Matthew B, Park, Kwang Hwan, Oh, Hwanhee, Ghosh, Sankar, Shim, Jae-Hyuck. 2015. CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts. In The Journal of experimental medicine, 212, 1283-301. doi:10.1084/jem.20150407. https://pubmed.ncbi.nlm.nih.gov/26195726/

4. Shim, Jae-Hyuck, Xiao, Changchun, Hayden, Matthew S, Mellman, Ira, Ghosh, Sankar. . CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis. In The Journal of cell biology, 172, 1045-56. doi:. https://pubmed.ncbi.nlm.nih.gov/16567502/

5. Son, Francheska, Umphred-Wilson, Katharine, Shim, Jae-Hyuck, Adoro, Stanley. . Assessment of ESCRT Protein CHMP5 Activity on Client Protein Ubiquitination by Immunoprecipitation and Western Blotting. In Methods in molecular biology (Clifton, N.J.), 1998, 219-226. doi:10.1007/978-1-4939-9492-2_16. https://pubmed.ncbi.nlm.nih.gov/31250305/

6. Wi, Sae Mi, Min, Yoon, Lee, Ki-Young. 2016. Charged MVB protein 5 is involved in T-cell receptor signaling. In Experimental & molecular medicine, 48, e206. doi:10.1038/emm.2015.102. https://pubmed.ncbi.nlm.nih.gov/26821576/