Ubqln1, also known as ubiquilin 1, is a crucial protein involved in maintaining proteostasis. It functions in processes such as the proteasomal degradation pathway, interacting with various proteins to ensure proper cellular function [1,6]. Ubqln1 is important for multiple biological processes, including autophagy, mitochondrial biogenesis, and telomere maintenance, which are essential for cell survival, energy production, and genomic stability respectively [1,2,3,4]. Genetic models, like knockout (KO) mouse models, have been instrumental in understanding its functions.

In hepatocytes, hepatocyte-specific cd36 knockout (cd36-HKO) mice showed improved liver injury and autophagosome-lysosome fusion in septic conditions. However, Ubqln1 overexpression (OE) in hepatocytes blocked this protective effect, indicating that CD36 modulates the proteasomal degradation of autophagic SNARE proteins in a Ubqln1-dependent manner, contributing to septic liver injury [1]. In hepatocellular carcinoma, sorafenib-resistant cells had upregulated Ubqln1, which induced the degradation of PGC1β in a ubiquitination-independent manner, attenuating mitochondrial biogenesis and ROS production, and thus mediating sorafenib resistance [2]. In idiopathic pulmonary fibrosis (IPF), UBQLN1 deficiency in mice led to telomere shortening in the lung and accelerated lung fibrosis, as UBQLN1 is involved in DNA replication by interacting with RPA1 and maintaining telomere stability [3]. In human embryonic stem cells, UBQLN1-deficient cells had telomere attrition, oxidative stress, and loss of proteostasis, suggesting UBQLN1 is critical for telomere maintenance via promoting mitochondrial function [4]. In colorectal cancer, knockdown of Ubqln1 in nude mice inhibited CRC cells' tumorigenesis and metastasis in vivo, and reduced the expression of c-Myc by downregulating the ERK-MAPK pathway, indicating Ubqln1 may be a potential prognostic biomarker and therapeutic target [5].

In conclusion, Ubqln1 plays essential roles in multiple biological processes, such as autophagy, mitochondrial biogenesis, telomere maintenance, and CRC progression. The study of Ubqln1 using KO mouse models has provided valuable insights into its functions in disease conditions like septic liver injury, hepatocellular carcinoma, IPF, and CRC, contributing to our understanding of disease mechanisms and potentially guiding the development of new therapeutic strategies.

References:

1. Li, Yanping, Xu, Jingyuan, Chen, Weiting, Ruan, Xiong Z, Zhao, Lei. 2023. Hepatocyte CD36 modulates UBQLN1-mediated proteasomal degradation of autophagic SNARE proteins contributing to septic liver injury. In Autophagy, 19, 2504-2519. doi:10.1080/15548627.2023.2196876. https://pubmed.ncbi.nlm.nih.gov/37014234/

2. Xu, Junjie, Ji, Lin, Ruan, Yeling, Liang, Xiao, Cai, Xiujun. 2021. UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma. In Signal transduction and targeted therapy, 6, 190. doi:10.1038/s41392-021-00594-4. https://pubmed.ncbi.nlm.nih.gov/34001851/

3. Zhou, Haoxian, Xie, Chen, Xie, Yujie, Zhao, Yong, Liu, Haiying. 2023. UBQLN1 deficiency mediates telomere shortening and IPF through interacting with RPA1. In PLoS genetics, 19, e1010856. doi:10.1371/journal.pgen.1010856. https://pubmed.ncbi.nlm.nih.gov/37463174/

4. Zhao, Shuang, Li, Jie, Duan, Songqi, Sun, Baofa, Liu, Lin. 2024. UBQLN1 links proteostasis and mitochondria function to telomere maintenance in human embryonic stem cells. In Stem cell research & therapy, 15, 180. doi:10.1186/s13287-024-03789-y. https://pubmed.ncbi.nlm.nih.gov/38902824/

5. Ni, Ruoxuan, Jiang, Jianwei, Zhao, Mei, Huang, Shengkai, Huang, Changzhi. 2023. Knockdown of UBQLN1 Functions as a Strategy to Inhibit CRC Progression through the ERK-c-Myc Pathway. In Cancers, 15, . doi:10.3390/cancers15123088. https://pubmed.ncbi.nlm.nih.gov/37370699/

6. Buel, Gwen R, Chen, Xiang, Myint, Wazo, Matsuo, Hiroshi, Walters, Kylie J. 2023. E6AP AZUL interaction with UBQLN1/2 in cells, condensates, and an AlphaFold-NMR integrated structure. In Structure (London, England : 1993), 31, 395-410.e6. doi:10.1016/j.str.2023.01.012. https://pubmed.ncbi.nlm.nih.gov/36827983/