K29‐Linked Ubiquitination of Transcription Regulators Controls Cell Proliferation in the Unfolded Protein Response

The ubiquitin chains perform diverse biological functions through different linkages. However, the understanding of non-canonical K29-linked ubiquitin chains is relatively limited. Exploring the physiological functions of K29-linked ubiquitin chains beyond degradation is crucial for deciphering the ubiquitin chain code, which is essential for understanding cellular physiology. The unfolded protein response (UPR) serves as a crucial mechanism for cells to cope with endoplasmic reticulum stress and involves comprehensive and precise regulation. Ubiquitin, as a regulator of protein function, has potential regulatory functions other than guiding protein degradation in the UPR. Here, a close association is revealed between K29-linked ubiquitin chains and transcriptional regulation during the UPR. After UPR induction, the K29-linked ubiquitination of the SMC1A and SMC3 proteins in the cohesin complex increases. The transcription of cell proliferation-related genes, such as SERTAD1 and NUDT16L1, is regulated by the K29-linked ubiquitination of cohesin. Overall, the upregulation of K29-linked ubiquitination of cohesin during the UPR disrupts the formation of the transcription initiation complex, resulting in the transcriptional downregulation of cell proliferation-related genes.