RUBCN, also known as Rubicon, is a protein encoded by the Rubcn gene. It contains a RUN domain and cysteine-rich domain and is a Beclin 1-interacting protein. It is an important negative regulator of autophagy, a lysosomal degradation system, which inhibits the fusion of autophagosomes and lysosomes, thus playing a role in regulating autophagy-related pathways [2,3,5,6]. Genetic models, such as KO mouse models, are valuable for studying its functions.

In PTEC-specific rubcn-deficient (KO) mice, although there was sustained high autophagic flux in PTECs, they were not protected from acute ischemic kidney injury. Instead, these KO mice showed features of metabolic syndrome, along with expanded lysosomes containing multi-layered phospholipids in PTECs. The deficiency promoted the mobilization of phospholipids from cellular membranes to lysosomes via enhanced autophagy, and accelerated fatty acids transfer to mitochondria and triglyceride accumulation in co-cultured hepatocytes [1]. In adipocytes, adipose-specific rubcn-knockout mice exhibited systemic fat loss not accelerated by fasting. Fasting decreased adipose RUBCN levels, and autophagic degradation of RUBCN served as a feedforward system for autophagy induction during fasting, promoting a metabolic response to fasting [6]. In osteoblasts, deletion of Rubcn led to elevated autophagy, facilitating bone formation, osteoblast differentiation, and alleviating osteoporosis by accelerating autophagic degradation of NOTCH intracellular domain and down-regulating the NOTCH signaling pathway [5]. In B cells, specific deficiency of the longer RUBCN130 isoform enhanced autophagy and promoted memory B cell generation, while the shorter RUBCN100 isoform promoted autophagy [4]. In diabetic patients, RUBCN mRNA and serum protein levels were over-expressed and correlated with albuminuria, suggesting its potential as a biomarker for diabetic kidney disease [7].

In conclusion, Rubcn is a key regulator of autophagy with significant implications in multiple biological processes and disease conditions. Studies using KO/CKO mouse models have revealed its roles in metabolic syndrome, the fasting response, bone homeostasis, B-cell function, and as a biomarker in diabetic kidney disease. These findings contribute to our understanding of the biological functions of Rubcn and its potential as a therapeutic target or biomarker in related diseases.

References:

1. Matsuda, Jun, Takahashi, Atsushi, Takabatake, Yoshitsugu, Yoshimori, Tamotsu, Isaka, Yoshitaka. 2020. Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells. In Autophagy, 16, 1889-1904. doi:10.1080/15548627.2020.1712107. https://pubmed.ncbi.nlm.nih.gov/31944172/

2. Xu, Yinfeng, Wan, Wei. 2022. Acetylation in the regulation of autophagy. In Autophagy, 19, 379-387. doi:10.1080/15548627.2022.2062112. https://pubmed.ncbi.nlm.nih.gov/35435793/

3. Cai, Wei, Hu, Mengyan, Li, Chunyi, Lu, Yan, Lu, Zhengqi. 2022. FOXP3+ macrophage represses acute ischemic stroke-induced neural inflammation. In Autophagy, 19, 1144-1163. doi:10.1080/15548627.2022.2116833. https://pubmed.ncbi.nlm.nih.gov/36170234/

4. Tsai, Chao-Yuan, Sakakibara, Shuhei, Kuan, Yu-Diao, Yoshimori, Tamotsu, Kikutani, Hitoshi. 2023. Opposing roles of RUBCN isoforms in autophagy and memory B cell generation. In Science signaling, 16, eade3599. doi:10.1126/scisignal.ade3599. https://pubmed.ncbi.nlm.nih.gov/37725663/

5. Yoshida, Gota, Kawabata, Tsuyoshi, Takamatsu, Hyota, Kumanogoh, Atsushi, Yoshimori, Tamotsu. 2022. Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis. In Autophagy, 18, 2323-2332. doi:10.1080/15548627.2021.2017587. https://pubmed.ncbi.nlm.nih.gov/35025696/

6. Yamamuro, Tadashi, Nakamura, Shuhei, Yanagawa, Kyosuke, Shimomura, Iichiro, Yoshimori, Tamotsu. 2022. Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response. In Autophagy, 18, 2686-2696. doi:10.1080/15548627.2022.2047341. https://pubmed.ncbi.nlm.nih.gov/35282767/

7. Watany, Mona M, El-Horany, Hemat E, Elhosary, Marwa M, Elhadidy, Ahmed A. 2022. Clinical application of RUBCN/SESN2 mediated inhibition of autophagy as biomarkers of diabetic kidney disease. In Molecular medicine (Cambridge, Mass.), 28, 147. doi:10.1186/s10020-022-00580-8. https://pubmed.ncbi.nlm.nih.gov/36476132/