The general transcription factor TFIIB is a target for transcriptome control during cellular stress and viral infection.

Many stressors, including viral infection, induce a widespread suppression of cellular RNA polymerase II (RNAPII) transcription, yet the mechanisms underlying transcriptional repression are not well understood. Here we find that a crucial component of the RNA polymerase II holoenzyme, general transcription factor IIB (TFIIB), is targeted for post-translational turnover by two pathways, each of which contribute to its depletion during stress. Upon DNA damage, translational stress, apoptosis, or replication of the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), TFIIB is cleaved by activated caspase-3, leading to preferential downregulation of pro-survival genes. TFIIB is further targeted for rapid proteasome-mediated turnover by the E3 ubiquitin ligase TRIM28. KSHV counteracts proteasome-mediated turnover of TFIIB, thereby preserving a sufficient pool of TFIIB for transcription of viral genes. Thus, TFIIB may be a lynchpin for transcriptional outcomes during stress and a key target for nuclear replicating DNA viruses that rely on host transcriptional machinery. Transcription by RNA polymerase II (RNAPII) synthesizes all cellular protein-coding mRNA. Many cellular stressors and viral infections dampen RNAPII activity, though the processes underlying this are not fully understood. Here we describe a two-pronged degradation strategy by which cells respond to stress by depleting the abundance of the key RNAPII general transcription factor, TFIIB. We further demonstrate that an oncogenic human gammaherpesvirus antagonizes this process, retaining enough TFIIB to support its own robust viral transcription. Thus, modulation of RNAPII machinery plays a crucial role in dictating the outcome of cellular perturbation.