Acetylation-dependent control of SIAH2 links JAK2V617F to mitochondrial respiration and ROS-associated apoptosis

Epigenetic modulators of the histone deacetylase (HDAC) family control key biological processes. We used leukemic cells with the constitutively active kinase oncoprotein JAK2 ^V617F as models to define the incompletely understood control of cytoplasmic signaling and cell organelles by nuclear HDACs. We reveal that HDAC1 and HDAC2 control JAK2 ^V617F through the ubiquitin-ligase seven-in-absentia-homologue-2 (SIAH2). Inhibition of HDAC1/HDAC2 stabilizes SIAH2 and accelerates proteasomal degradation of JAK2 ^V617F which has a surface-exposed SIAH degron motif in its catalytic domain. This acetylation-dependent loss of JAK2 ^V617F and its downstream signaling to the inducible transcription factor STAT1 disrupts expression of the mitochondrial chaperone SMIM20. Consequently, inactivation of HDAC1 and HDAC2 disengages the electron transport chain of oxidative phosphorylation and causes ROS-associated, pro-apoptotic DNA damage. This study links the nuclear located HDAC1/HDAC2 to JAK-STAT-dependent mitochondrial functions, redox homeostasis, and genomic stability.