Regulatory Protein Induction by Arsenite Aids Proteasomes in Proteotoxicity

David Ron, MD
SSkirball Institute of Biomolecular Medicine, NYU School of Medicine
NIEHS Grant R01ES008681

New NIEHS-supported basic research demonstrates that an arsenic-induced regulatory protein known as AIRAP adapts the cellular protein degradation machinery in the proteasome to help rid the cell of accumulated damaged proteins in response to environmental toxins.

The accumulation of damaged proteins is a characteristic of aging cells. Unless these proteins are repaired or removed from cells, they often impair proper cell function and can lead to cell death. Proteasomes are protein degradative machines that are found in the nucleus and the cytoplasm and are involved in many cellular processes including the removal of abnormal and misfolded proteins, degradation of ubiquitin-conjugated regulatory proteins, regulation of the cell cycle, and cellular differentiation by degrading transcription factors and metabolic enzymes. Research has shown that they are essential to life because removal of proteasome genes in eukaryotic cells is lethal.

AIRAP is a gene found in many cell types and is selectively activated by arsenite, an ionic form of arsenic. Using the nematode C. elegans, these investigators determined that AIRAP is induced by arsenite but not other conditions that impede proper protein folding. According to the authors, ”AIRAP associates tightly with the 19S cap of the proteasome, altering its biochemical properties.”

Citation: Stanhill A, Haynes CM, Zhang Y, Min G, Steele MC, Kalinina J, Martinez E, Pickart CM, Kong XP, Ron D. An arsenite-inducible 19S regulatory particle-associated protein adapts proteasomes to proteotoxicity. Mol Cell. 2006 Sep 15;23(6):875-85.