Polysulfides promote ATF6 oligomerization via persulfidation to modulate ER stress responses

ATF6 is a UPR sensor regulated by redox modification of luminal cysteine residues. Although polysulfides modulate proteins through cysteine persulfidation, their effect on ATF6 has been unclear. Here, we show that polysulfides rapidly induce ATF6 oligomerization and inhibit its nuclear translocation in SH-SY5Y cells. We identify Cys618 as a persulfidation site, supporting a distinct redox mechanism for ATF6 inactivation. Our results further indicate that, although suppression of the ATF6 pathway is generally expected to increase vulnerability to ER stress, polysulfide-mediated suppression of the ATF6 pathway did not exacerbate tunicamycin-induced cytotoxicity under our experimental conditions. These findings reveal polysulfide-mediated persulfidation as a previously unrecognized mechanism regulating ATF6 and provide insight into how polysulfides modulate UPR signaling and cellular adaptation to ER stress.