HSF4 promotes lipid peroxidation by transcriptionally regulating ALOX15 during lens terminal differentiation

Lens fibers undergo organelle degradation during lens terminal differentiation. Defects in organelle degradation of lens fibers lead to congenital cataract. As a member of heat shock factor family, HSF4 governs lens development by regulating the expression of key factors. HSF4 transcriptionally regulates ATG9a to induce organelle degradation via the autophagic pathway during lens terminal differentiation. HSF4 is also required for the organelle membrane translocation of phospholipases PLAATs, which were suggested to promote organelle degradation independent of autophagy in lens fibers. However, the detailed mechanism how HSF4 induces organelle degradation in lens fibers still remains unknown. In this study, we found that lipid peroxidation was extensively suppressed in HSF4^del42 mouse lens fibers. HSF4 likely transcriptionally regulated the expression of lipoxygenase ALOX15 in lens. ALOX15 is uniquely expressed in lens fibers and colocalized with organelles in differentiating lens fibers. Knockout of ALOX15 had little effect on the organelle degradation in lens fibers. Unlike the total inhibition in HSF4^del42 lens fibers, lipid peroxidation was only partially disturbed in ALOX15^-/- lens fibers, possibly due to the compensatory role of ALOX12. Our findings demonstrate that HSF4 promotes lipid peroxidation by transcriptionally regulating ALOX15 expression in lens fibers, thus may contribute to the organelle degradation during lens OFZ formation. These findings expand our understanding of the molecular mechanisms underlying lens terminal differentiation.