Transcriptomic characterization of Lonrf1 at the single-cell level under pathophysiological conditions.

The LONRF family of proteins consists of three isozymes, LONRF1-3. We have recently identified LONRF2 as a protein quality control ubiquitin ligase that acts predominantly in neurons. LONRF2 selectively ubiquitylates misfolded or damaged proteins for degradation. LONRF2-/- mice exhibit late-onset neurological deficits. However, the physiological implications of other LONRF isozymes remain unclear. Here, we analyzed Lonrf1 expression and transcriptomics at the single-cell level under normal and pathological conditions. We found that Lonrf1 was ubiquitously expressed in different tissues. Its expression in LSEC and Kupffer cells increased with age in the liver. Lonrf1high Kupffer cells showed activation of regulatory pathways of peptidase activity. In normal and NASH liver, Lonrf1high LSECs showed activation of NF-κB and p53 pathways and suppression of IFNα, IFNγ, and proteasome signaling independent of p16 expression. During wound healing, Lonrf1high/p16low fibroblasts showed activation of cell growth and suppression of TGFβ and BMP signaling, whereas Lonrf1high/p16high fibroblasts showed activation of WNT signaling. These results suggest that although Lonrf1 does not appear to be associated with senescence induction and phenotypes, LONRF1 may play a key role in linking oxidative damage responses and tissue remodeling during wound healing in different modes in senescent and non-senescent cells.