Orphan quality control shapes network dynamics and gene expression

Abstract

All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb crucial interactions between network components often result in disease, but how the composition and dynamics of complex networks are established is unknown. Here, we identify the tumor suppressor E3 ligase UBR5 as a quality control enzyme that helps degrade unpaired subunits of multiple transcription factors that operate within a single network. By constantly turning over orphan subunits, UBR5 forces cells to continuously replenish network components through new protein synthesis. The resulting cycles of transcription factor synthesis and degradation allow cells to effectively execute the gene expression program, while remaining susceptible to environmental signals. We conclude that orphan quality control plays an essential role in establishing the dynamics of protein networks, which may explain the conserved need for protein degradation in transcription and offers unique opportunities to modulate gene expression in disease.

Surprising Features of Nuclear Receptor Interaction Networks Revealed by Live Cell Single Molecule Imaging

“…We favor the latter possibility because overexpression of RAR reduces not only the expression of endogenous RAR but also its fbound (Figure 2F), indicating a reduction in dimerization and chromatin binding. It is possible that endogenous RAR may be more readily degraded when not bound by RXR, analogous to what was recently shown for the c-MYC/MAX heterodimers (Mark et al, 2023). Second, as has been previously reported, RAR expression decreases upon ligand treatment (Kopf et al, 2000;Osburn et al, 2001;Zhu et al, 1999;Ismail & Nawaz, 2005;Tsai et al, 2023).…”

Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity

“…Supporting this idea, recent structural studies of HUWE1 have revealed three distinct substrate binding domains 106,107 , facilitating the recognition and ubiquitination of unbound nucleic acid binding proteins as well as ubiquitinated/PARylated substrates. Similarly, UBR5 was recently shown to bind and ubiquitinate unengaged transcription factors 87 , and has the ability to function as a ubiquitin chain elongating E4 90,91 . In combination with our findings in this study, these results indicate that HUWE1 and UBR5 are both important players in recognizing and degrading unengaged DNA-and RNA-binding proteins.…”

“…The three identified A3-targeting E3 ligases UBR5 [87][88][89][90][91][92] , HUWE 71,72,[93][94][95][96][97][98] , and UBR4 56,74,87,[99][100][101][102][103][104][105] , have previously been linked to the turn-over of a diverse array of substrates, thereby exerting control over numerous cellular processes. This suggests that these E3 ligases possess the ability to identify multiple substrate classes based on broad biochemical or biophysical characteristics.…”

Structural mechanisms of autoinhibition and substrate recognition by the ubiquitin ligase HACE1

“…Chemical biology and selective crosslinking approaches provided access to the first cryo-EM structural views of mutisubunit ubiquitin ligase complexes with substrate-derived peptides (e.g., [4][5][6][7][8] ). Moreover, structures of a small number of full-length ligases were determined with substrate proteins or domains thereof (e.g., [9][10][11][12][13][14][15] ). Most of these complexes contain RING-type E3s that function as catalytic scaffolds, facilitating direct Ub transfer from an E2 to a substrate 16 .…”

“…Yet, how these motifs orient substrates toward the catalytic center within the full-length ligases has not been visualized structurally. Recently, UBR5 was shown to utilize the HECT domain to sandwich substrates between subunits within a ligase tetramer 12,13 . For other HECT-type ligases, however, the catalytic domain per se is insufficient for the recruitment of substrates, and the significance of oligomerization for substrate binding is still unknown.…”