Sumo and the cellular stress response

Abstract

The ubiquitin family member Sumo has important functions in many cellular processes including DNA repair, transcription and cell division. Numerous studies have shown that Sumo is essential for maintaining cell homeostasis when the cell encounters endogenous or environmental stress, such as osmotic stress, hypoxia, heat shock, genotoxic stress, and nutrient stress. Regulation of transcription is a key component of the Sumo stress response, and multiple mechanisms have been described by which Sumo can regulate transcription. Although many individual substrates have been described that are sumoylated during the Sumo stress response, an emerging concept is modification of entire complexes or pathways by Sumo. This review focuses on the function and regulation of Sumo during the stress response.

Keywords: DNA damage response; ER stress; Nutrient stress; SIMs; Stress response; Sumo; Transcription; Viral infections.

Fig. 1

Overview of the Sumo pathway

Fig. 2

Regulation of PCNA by ubiquitin and Sumo. When cells are treated with high doses of MMS, PCNA becomes Sumo-modified primarily on K164 and to a lesser extent K127, resulting in recruitment of HR inhibitor Srs2. At lower levels of DNA damage PCNA is ubiquitinated mainly on K164 (and to a lesser degree also on other sites [113, 51]). This promotes lesion bypass in case of monoubiquitination, whereas polyubiquitinated PCNA induces template switching and error-free DNA repair

Fig. 3

Viruses can target the Sumo pathway to disrupt PML-NBs. a, Several components of PML-NBs are targets of Sumo, and multiple Sumo-SIM interactions may promote complex stability. b, The HSV viral protein ICP0 can function as a STUBL to degrade sumoylated PML, thereby disrupting structural integrity of PML-NBs

Fig. 4

Sumo and the ER stress response. Unfolded proteins trigger the ER stress response, inducing processing of XBP mRNA by Ire1, ultimately yielding active XBP1s. Sumoylation of XBP1s and the physical interaction with Ubc9 inhibit its transcriptional activity

Fig. 5

Multiple mechanisms of transcriptional regulation by Sumo. a, Sumoylation prevents nuclear entry. b, Sumo prevents recruitment of general transcription factors (GTFs). c, Sumo inhibits promoter binding of the transcription factor. d, Sumo competes with other modifications that activate transcription. e, Sumo prevents degradation of an inhibitor of a transcription factor. f, Sumo recruits a transcriptional repressor that silences the local chromatin environment. g, Sumoylation increases the activity of a transcriptional repressor to inhibit transcription

Fig. 6

Regulation of pro-growth genes by Sumo. a, in the presence of sufficient nutrients, TORC1 and Ubc9 in transcription of pro-growth genes like RPGs and tRNA genes. TORC1 increases phosphorylation of Sfp1 and Ifh1, leading to their recruitment to PRG promoters. Ubc9 sumoylates Rap1, which enhances recruitment of TFIID to RPGs. Ubc9 also sumoylates RNAPIII components, which most likely is required for efficient tRNA transcription. TORC1 increases phosphorylation of Maf1, resulting in its nuclear exclusion. b, During nutrient stress TORC1 is inactive, leading to dephosphorylation of Sfp1 and Ifh1, which are then released from RPG promoters. Maf1 also becomes dephosphorylated, resulting in its nuclear entry where it binds and inhibits RNAPIII. At least in mammals Maf1 is also sumoylated, which contributes to its repressive effect on RNAPIII. Whether this also occurs in yeast is unknown