MED26 facilitates Mediator–Pol II complex assembly and promotes nuclear stress body formation during heat stress

Cells adapt to environmental stress by reprogramming gene expression. During heat stress, the transcription factor HSF1 translocates into the nucleus and activates heat shock–responsive genes, including the lncRNA HSATIII, thereby promoting formation of nuclear stress bodies (nSBs). We show that the Mediator subunit MED26 enhances HSATIII transcription and nSB formation through a mechanism distinct from its role at canonical heat shock protein (HSP) genes. Upon heat stress, MED26-containing Mediator is recruited to both HSP loci and nSBs through interactions with HSF1 and MED15. Notably, phosphorylation of the intrinsically disordered region (IDR) of HSF1 is particularly important for Mediator recruitment to nSBs. Acute loss of MED26 leads to dissociation of both Mediator and Pol II from HSP promoters, whereas at HSATIII loci Mediator is retained despite Pol II dissociation. These results indicate that MED26 acts as molecular switch that facilitates Mediator-Pol II holo-complex assembly at nSBs and promotes nSB formation during heat stress.