Ubxn6, short for Ubiquitin regulatory X (UBX) domain-containing protein 6, is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. It is involved in multiple cellular pathways, such as autophagy, endoplasmic reticulum-associated degradation, and JAK-STAT1/2 signaling, which are crucial for maintaining cellular homeostasis and immune responses [1,2].

In myeloid cell-specific UBXN6-depleted mice, macrophages showed exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also underwent immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic changes amplified mammalian target of rapamycin pathway signaling, reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis [1]. In human UBXN6-deficient cells, RNA viral replication increased, accompanied by a reduction in both type I/III IFN expression, indicating its role in antiviral responses [2].

In summary, Ubxn6 serves as an activator of autophagy, regulates inflammation, and is important for maintaining normal JAK-STAT1/2 signaling during immune responses. The study of Ubxn6 using gene knockout models, like the myeloid cell-specific UBXN6-depleted mice, has provided valuable insights into its role in sepsis-related inflammation and viral infection, highlighting its potential as a therapeutic target in these disease areas [1,2].

References:

1. Kim, Young Jae, Lee, Sung-Gwon, Park, So Young, Paik, Seungwha, Jo, Eun-Kyeong. 2024. Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages. In Cellular & molecular immunology, 21, 1441-1458. doi:10.1038/s41423-024-01222-1. https://pubmed.ncbi.nlm.nih.gov/39438692/

2. Ketkar, Harshada, Harrison, Andrew G, Graziano, Vincent R, Vella, Anthony T, Wang, Penghua. 2021. UBX Domain Protein 6 Positively Regulates JAK-STAT1/2 Signaling. In Journal of immunology (Baltimore, Md. : 1950), 206, 2682-2691. doi:10.4049/jimmunol.1901337. https://pubmed.ncbi.nlm.nih.gov/34021047/