Fleming, J. R. | bioRxiv Science

bioRxiv2023

Liver Receptor Homolog-1 (LRH-1/NR5A2) orchestrates hepatic inflammation and TNF-induced cell death

Liver Receptor Homolog-1 (LRH-1/NR5A2) is a nuclear receptor that has been shown to promote apoptosis resistance in various tissues and disease contexts, however, its role in liver cell death remains unexplored. Deletion of LRH-1 in hepatocytes developed into a mild steatosis and inflammation already under steady-state conditions. Unexpectedly, hepatocyte-specific deletion of LRH-1 also resulted in a profound protection of mice from TNF-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes showed elevated NF-B activity, while LRH-1 overexpression inhibited NF-B activity. This inhibition was based on direct physical interaction of the ligand-binding domain of LRH-1 and the Rel homology domain of NF-B subunit RelA. Mechanistically, we found that increased transcription of anti-apoptotic NF-B target genes, together with proteasomal degradation of pro-apoptotic BIM via regeneration-driven EGF receptor signaling, prevented mitochondrial apoptosis, ultimately protecting mice from TNF-induced liver damage. Collectively, our study demonstrates that LRH-1 is a critical modulator of cell death and inflammation in the healthy and diseased liver. HighlightsO_LIHepatic LRH-1 deletion causes mild liver steatosis, fibrosis, and inflammation. C_LIO_LIFemale LRH-1-deficient mice are protected from TNF-induced liver damage. C_LIO_LILRH-1 interacts with NF-B and inhibits its activity. C_LIO_LILRH-1 deletion-provoked inflammation causes degradation of pro-apoptotic protein BIM. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/542039v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@13cd609org.highwire.dtl.DTLVardef@1080012org.highwire.dtl.DTLVardef@3cd9c4org.highwire.dtl.DTLVardef@fd0438_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Pairwise sequence similarity mapping with PaSiMap: reclassification of immunoglobulin domains from titin as case study

Sequence comparison is critical for the functional assignment of newly identified protein genes. As uncharacterised protein sequences accumulate, there is an increasing need for sensitive tools for their classification. Here, we present a novel multidimensional scaling pipeline, PaSiMap, which creates a map of pairwise sequence similarities. Uniquely, PaSiMap distinguishes between unique and shared features, allowing for a distinct view of protein-sequence relationships. We demonstrate PaSiMaps efficiency in detecting sequence groups and outliers using titins 169 immunoglobulin (Ig) domains. We show that Ig domain similarity is hierarchical, being firstly determined by chain location, then by the loop features of the Ig fold and, finally, by super-repeat position. The existence of a previously unidentified domain repeat in the distal, constitutive I-band is revealed. Prototypic Igs, plus notable outliers, are identified and thereby domain classification improved. This re-classification can now guide future molecular research. In summary, we demonstrate that PaSiMap is a sensitive tool for the classification of protein sequences, which adds a new perspective in the understanding of inter-protein relationships. PaSiMap is applicable to any biological system defined by a linear sequence, including nucleotides.

bioinformatics↗