Longevity & AgingNuclear Autophagy Protein WSTF Selectively Drives Chronic Inflammation
Researchers at MGH and collaborating institutions discovered that WSTF, a chromatin remodeling protein, is selectively degraded via nuclear autophagy during chronic inflammation. When the autophagy protein GABARAP binds WSTF in the nucleus, WSTF is exported to the cytoplasm and destroyed by autophagosomes/lysosomes. Loss of WSTF opens chromatin over inflammatory genes, amplifying the inflammatory response. Crucially, this mechanism operates during chronic inflammation—such as cellular senescence, metabolic liver disease (MASH), and osteoarthritis—but not during acute inflammation. Cell-penetrating peptides blocking the WSTF-GABARAP interaction suppressed chronic inflammation in mouse models and patient samples without impairing acute immune responses, suggesting a targeted therapeutic strategy for chronic inflammatory diseases.
