RUBCN, also known as Rubicon, is a key protein in the regulation of autophagy. It is a RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein. Autophagy is a lysosomal degradation system, and RUBCN inhibits the fusion of autophagosomes and lysosomes, thus playing a significant role in this important cellular pathway [1,2,3,4,5,6]. Genetic models, such as KO mouse models, have been crucial in studying the function of RUBCN.

In kidney proximal tubular epithelial cells (PTECs), PTEC-specific rubcn-deficient (KO) mice showed sustained high autophagic flux but were not protected from acute ischemic kidney injury. Instead, they exhibited features of metabolic syndrome, with expanded lysosomes containing multi-layered phospholipids in PTECs. In cultured PTECs, RUBCN deficiency promoted phospholipid mobilization from cellular membranes to lysosomes via enhanced autophagy [1]. In osteoblasts, rubcn-deficient mice (rubcnflox/flox;Sp7/Osterix-Cre) had progressive skeletal abnormalities. RUBCN deficiency in osteoblasts led to elevated differentiation and mineralization, accelerated autophagic degradation of NOTCH intracellular domain, and alleviated the phenotype in a mouse model of osteoporosis [4]. Adipose-specific rubcn-knockout mice had systemic fat loss, and loss of adipose RUBCN promoted a metabolic response to fasting via increased autophagic activity [6].

In conclusion, RUBCN is a critical regulator in autophagy, affecting various biological processes. The study of RUBCN-KO mouse models has revealed its role in metabolic syndrome, osteoporosis, and the fasting response. These findings provide insights into the underlying mechanisms of these conditions and may offer potential therapeutic targets.