Ubxn6, or 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, and is crucial for maintaining immune system balance and cellular homeostasis [1,2]. Genetic models, like gene knockout mouse models, are valuable for studying its functions.

In macrophages of mice with myeloid cell-specific UBXN6 depletion, there was exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also showed immunometabolic remodeling, reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis, revealing its role in autophagy induction and inflammation control during sepsis [1]. In human UBXN6-deficient cells, RNA viral replication was increased, accompanied by a reduction in both type I/III IFN expression, indicating its positive regulation of JAK-STAT1/2 signaling [2].

In conclusion, Ubxn6 is essential for autophagy induction, inflammation control, and the regulation of JAK-STAT1/2 signaling. The study of Ubxn6 knockout mouse models has revealed its significance in sepsis and antiviral immune responses, providing insights into the underlying mechanisms of these biological processes and potential therapeutic targets for related diseases.