RPL26 UFMylation deficiency triggers Paneth cell apoptosis associated with ER stress by impairing ATG16L1-dependent ER-phagy.

BACKGROUND

UFMylation plays an essential role in multiple physiological processes. Ribosomal protein L26 (RPL26), a principal target of UFMylation and a component of the ribosomal 60S subunit, is directly involved in protein synthesis. However, the biological significance of RPL26 UFMylation in intestinal epithelial cells (IECs) and intestinal homeostasis remains largely unknown.

METHODS

IEC-specific RPL26K132/134R mutant (RPL26 UFMylation deficiency) mouse model (CKI) were constructed to investigate the role of RPL26 UFMylation in intestinal development and homeostasis.

RESULTS

RPL26 UFMylation deficiency led to a loss of 70 kD and 25-35 kD UFMylated proteins, indicating reduced modification efficiency. Notably, CKI mice exhibited a significantly higher incidence of rectal prolapse and elevated inflammatory levels. More importantly, the small intestine and colon were markedly shortened, with a significant reduction in goblet and Paneth cells. Consistent with the loss of Paneth cells, lysozyme expression was profoundly decreased, accompanied by the downregulation of genes critical for Paneth cell differentiation, development, and lysozyme secretion. Further research found that RPL26 UFMylation deficiency suppressed endoplasmic reticulum aotophagy (ER-phagy) by promoting the ubiquitin-mediated degradation of autophagy related 16 like 1 (ATG16L1), consequently triggering ER stress-dependent apoptosis in Paneth cells.

CONCLUSION

Our findings reveal a critical role for RPL26 UFMylation in maintaining IEC function and intestinal homeostasis, providing novel insights into the genetic mechanisms underlying intestinal health.