Ubiquitin system

The complexities of the ubiquitin system are fully described in Nature 2009 vol 458 pages 422 to 467.

Page 422 Hochstrasser Origin and function of ubiquitin-like proteins.
The function of proteins can be modulated through a wide array of post-translational modifications. One such modification in eukaryotic cells is ubiquitylation – the covalent attachment of a small, highly conserved protein called ubiquitin to other proteins, either
as a monomer or in polymeric chains. Increasing evidence indicates that this system has evolved from the sulphurtransferase system that operates in prokaryotes. Furthermore, protein-sequence comparison and structural analysis indicate that bacteria contain many ubiquitin-like proteins.
Page 430 Bhoj &. Chen Ubiquitylation in innate and adaptive immunity
By attaching to a substrate through different linkages, ubiquitin can either target it to the proteasome for destruction or regulate its activity and localization. Ubiquitylation is extensively used in the initiation, amplification and termination of the immune response. One of the best studied examples is the activation of the nuclear factor-xb signalling pathway, which is important in both innate and adaptive immunity. Recent research has revealed the importance of the ubiquitin system in developing immune tolerance and thereby preventing autoimmune diseases.
Page 438 Hoeller & Dikic Targeting the ubiquitin system in cancer therapy .
Many of the cellular processes regulated by ubiquitylation – such as cell-cycle progression, apoptosis, receptor downregulation and gene transcription – are relevant to tumorigenesis. Deregulation of the ubiquitin system is implicated in the initiation and progression of various cancers. A knowledge of which components of the system are affected in what cancer could not only aid in the development of new anticancer agents, but also be relevant to diagnosis. Efforts are already underway to target components of the ubiquitin system that are affected in cancer, with stories of both success and failure abounding.
Page 445. Raiborg & Stenmark The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins .
Membrane proteins destined for degradation are delivered to lysosomes by way of multivesicular endosomes (MVEs). Ubiquitylation ensures that these proteins are sorted into vesicles within the endosomal lumen. The endosomal sorting complex required for transport (ESCRT) performs three main functions. It recognizes ubiquitylated cargo, deforms the endosomal membrane and catalyses the final abscission of the invaginations to form intraluminal vesicles that contain the cargo. The resultant MVE eventually fuses with Iysosomes, where cargo is degraded. In addition to MVE biogenesis, the E5CRT machinery is involved in diverse processes such as viral budding, cytokinesis and autophagy and protects against disorders such as neurodegeneration and cancer.
Page 453 Hirsch, Gauss, Horn, Neuber & Sommer The ubiquitylation machinery of the endoplasmic reticulum
Newly synthesized proteins are transported to the endoplasmic reticulum (ER), where an array of molecular chaperones guide and assist the proteins in their maturation. Proteins that do not reach their native conformation owing to mutations or to errors in transcription or translation, as well as mature proteins that have been damaged by environmental conditions such as highenergy radiation, clog up the ER, impairing its efficiency. The ER therefore uses a quality-control system, consisting of glycan codes and the ubiquitin system, to identify the defective proteins and transport them out of the organelle to the cytoplasm for destruction.
Page 461 Bergink & Jentsch Principles of ubiquitin and SUMO modifications in DNA repair .
Within the cell, ubiquitylation, and the related process SUMOylation, affect all major DNA-repair pathways, damage-avoidance mechanisms and checkpoint responses in one way or another.
For instance, ubiquitin and SUMO molecules can tag for degradation either stalled enzymes or proteins that have completed their DNA-repair function. As maintenance of genomic stability is essential for health, dysfunction of the ubiquitin and SUMO systems has been associated with a range of diseases linked to inefficient DNA repair, including cancer and Fanconi anaemia.

Martin Eastwood
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