Rufy4, a member of the 'RUN and FYVE domain-containing' protein family, is involved in multiple cellular processes. It plays a role in autophagy and intracellular trafficking, and is associated with pathways like endo-lysosomal trafficking. It has significance in the immune system and bone-related biology, making genetic models valuable for studying its functions [2,3,4,5].

In gene knockout studies, mice lacking Rufy4 showed a high trabecular bone mass phenotype due to abnormal osteoclast function. Deleting Rufy4 did not affect osteoclast differentiation but inhibited bone-resorbing activity by disrupting secondary lysosome acidic maturation, their trafficking to the membrane, and secretion of cathepsin K. Mechanistically, RUFY4 promotes late endosome-lysosome fusion. Thus, Rufy4-deficient mice were protected from lipopolysaccharide-and ovariectomy-induced bone loss [1]. Another study using siRNA and over-expression systems in osteoclasts found that silencing Rufy4 enhanced osteoclast differentiation and intracellular cathepsin K levels but suppressed bone resorption, while over-expressing wild-type Rufy4 had the opposite effects, indicating its role in osteoclast differentiation and bone resorption by regulating cytoskeletal organization through its RUN domain [5].

In conclusion, Rufy4 is crucial for regulating autophagy, intracellular trafficking, and specifically, osteoclast-mediated bone resorption. The use of Rufy4 knockout mouse models has provided key insights into its role in preventing pathological bone loss, suggesting its potential as a target for treating bone-loss diseases like osteoporosis.

References:

1. Kim, Minhee, Park, Jin Hee, Go, Miyeon, Shim, Hyunbo, Lee, Soo Young. 2024. RUFY4 deletion prevents pathological bone loss by blocking endo-lysosomal trafficking of osteoclasts. In Bone research, 12, 29. doi:10.1038/s41413-024-00326-8. https://pubmed.ncbi.nlm.nih.gov/38744829/

2. Valečka, Jan, Camosseto, Voahirana, McEwan, David G, Gatti, Evelina, Pierre, Philippe. 2021. RUFY4 exists as two translationally regulated isoforms, that localize to the mitochondrion in activated macrophages. In Royal Society open science, 8, 202333. doi:10.1098/rsos.202333. https://pubmed.ncbi.nlm.nih.gov/34295519/

3. Terawaki, Seigo, Camosseto, Voahirana, Pierre, Philippe, Gatti, Evelina. . RUFY4: Immunity piggybacking on autophagy? In Autophagy, 12, 598-600. doi:10.1080/15548627.2015.1136772. https://pubmed.ncbi.nlm.nih.gov/26760128/

4. Keren-Kaplan, Tal, Sarić, Amra, Ghosh, Saikat, Li, Yan, Bonifacino, Juan S. 2022. RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin. In Nature communications, 13, 1506. doi:10.1038/s41467-022-28952-y. https://pubmed.ncbi.nlm.nih.gov/35314674/

5. Sakai, Eiko, Saito, Minoru, Koyanagi, Yu, Yamaguchi, Yu, Tsukuba, Takayuki. 2024. Autophagy Regulator Rufy 4 Promotes Osteoclastic Bone Resorption by Orchestrating Cytoskeletal Organization via Its RUN Domain. In Cells, 13, . doi:10.3390/cells13211766. https://pubmed.ncbi.nlm.nih.gov/39513873/