SP110 PROTECTS CELLS FROM INTEREFERON-INDUCED CELL DEATH- PUBLISHED IN NATURE CELL BIOLOGY

Stimulation of the innate immune system by foreign RNA triggers a strong interferon response that helps cells defend against infection. However, this powerful defense mechanism can also lead to cell death if not properly controlled. How do cells maintain this delicate balance?

Our latest breakthrough was led by postdoc Eric Aird in collaboration with the Hale Lab (University of Zurich), Recher Lab (University of Basel, University Hospital Basel), Jackson Lab (UCAM) and University of Kuwait.

Using genome-wide CRISPR screens and follow-up cellular biochemistry experiments, we discovered that speckled protein 110 (SP110) functions as a key safeguard against cell death triggered by interferon signaling.

Mechanistically, the study revealed that SP110 interacts with the nuclear body protein SP100 to regulate the disassembly of nuclear promyelocytic leukemia (PML) bodies. Loss of SP110 made cells highly sensitive to interferon stimulation, led to mitotic retention of SP100 and PML bodies, which associated with and perturb segregating chromosomes, leading to micronucleus formation, DNA damage and genotoxic cell death. Conversely, restoring SP110 protected cells from this lethal response. The SP100-SP110 axis is molecularly achieved by newly described functions for the SP100 and SP110 CARD domains that mediate assembly and disassembly of SP100 oligomers. By controlling this process, SP110 helps maintain a balance between effective immune signaling and cell survival.

These findings highlight regulated disassembly of phase-separated biomolecular bodies as essential for cell health and that its failure may contribute to diverse human diseases.

For more details, please visit Nature Cell Biology!