Cell signalling

PARP-1 attenuates Smad-mediated transcription Lönn, P. et al. Mol. Cell 40, 521–532 (2010)

Transforming growth factor-β (TGFβ) activates receptors to phosphorylate SMAD2 and SMAD3, enabling them to form a complex with SMAD4. This complex coordinates SMAD-activated transcription until transcription is terminated by the dephosphorylation, nuclear export or degradation of SMADs. Lönn et al. now show that poly(ADP-ribose) polymerase 1 (PARP1) — which covalently attaches ADP-ribose to substrates during poly(ADP-ribosyl)ation (PARylation) — can also terminate SMAD-activated transcription. PARP1 interacts with SMAD2, SMAD3 and SMAD4 in the nucleus, in response to TGFβ, and induces the PARylation of SMAD3 and SMAD4 in vitro and in vivo. This reduces the amount of SMAD3–SMAD4 bound to DNA, and attenuates the effects of SMADs on transcription. Depletion of PARP1 enhances the TGFβ-induced transdifferentiation of epithelial cells to mesenchymal cells, suggesting that PARylation can regulate SMADs in physiological settings. Thus, SMAD PARylation can also terminate SMAD-mediated transcription.

Post-translational modification

β- N -acetylglucosamine (O-GlcNAc) is part of the histone code Sakabe, K., Wang, Z. & Hart, G. W. Proc. Natl Acad. Sci. USA 107, 19915–19920 (2010)

The dynamic post-translational modification of proteins on Ser and Thr by β-N-acetylglucosamine (O-GlcNAc) can regulate processes such as transcription and cell signalling. This study identifies histones as novel substrates of O-GlcNAcylation. The authors show that histones are modified by O-GlcNAc in vitro and in vivo; histone 2A (H2A), H2B and H4 are modified on Thr101, Ser36 and Ser47, respectively. To determine whether histone O-GlcNAcylation is dynamic, and thus might have a biological role, the authors assessed histone O-GlcNAc levels during mitosis and recovery after heat shock — two processes in which O-GlcNAc and histone modifications change dramatically. Histone O-GlcNAcylation decreases during mitosis and increases during the recovery after heat shock. Thus, the authors conclude that “O-GlcNAc cycles dynamically on histones and can be considered part of the histone code.”

Ubiquitylation

c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling Dynek, J. N. et al. EMBO J. 26 Nov 2010 (doi:10.1038/emboj.2010.300)

This study shows that, in addition to their role in degrading cell cycle proteins, atypical Lys11-linked ubiquitin chains might function in cell signalling. Receptor-interacting protein 1 (RIP1), which is involved in the tumour necrosis factor (TNF)-mediated activation of nuclear factor-κB (NF-κB) signalling, was modified with Lys11-linked chains by the E2 enzyme inhibitor of apoptosis 1 (IAP1); this is in addition to the known IAP-mediated ubiquitylation of RIP1 with canonical Lys43- and Lys68-linked chains. Canonical chains on RIP1 are crucial for recruiting NF-κB essential modulator (NEMO) to the TNF receptor complex, which is required for TNF-induced activation of NF-κB signalling. Interestingly, NEMO was found to bind Lys11-linked chains on RIP1 with similar affinity to canonical chains, indicating that Lys11-linked chains might have a role in NEMO recruitment and, consequently, in TNF-mediated signalling.