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The protein FAM134B is an endoplasmic reticulum (ER)-resident receptor that facilitates ER autophagy, and downregulation of this protein (mutations of which are also known to cause sensory neuropathy in humans) results in expanded ER structures and degeneration of mouse sensory neurons.

The ubiquitin conjugation system regulates the canonical NF-κB activation pathway, which mediates immune responses. Linear polyubiquitin chains—in which the C terminal glycine of ubiquitin is conjugated to the α-amino group of the amino-terminal methionine of another ubiquitin—are generated by a unique ubiquitin ligase complex called linear ubiquitin chain assembly complex (LUBAC) composed of two RING domain proteins called HOIL-1 and HOIP. This is one of three complementary studies identifying a novel component of the LUBAC complex called SHARPIN, which is recruited to receptor signalling complexes (RSCs) that form after TNF and CD40L stimulation. The LUBAC complex containing SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo and is required for the activation of NF-κB signalling.

After being used in the 1950s to treat morning sickness in pregnant women, with devastating effects, thalidomide and its derivatives (lenalidomide and pomalidomide) are now widely used in cancer therapy. New structural work from two groups gives insights into the basis for the teratogenicity and other clinical effects of these drugs.

In the shadow of societal upheaval and transformation, Eastern and South-Eastern European countries have been undergoing major reforms of their scientific and academic landscapes. Although the reforms have been slow, the success of several molecular biology institutes has highlighted what can be achieved.

The 26S proteasome is a multisubunit complex that selectively degrades ubiquitin conjugated proteins. Two studies (this Letter and the Article Dikic doi:10.1038/nature06926) show that a known component of the proteasome, Rpn13, functions as a novel ubiquitin binding receptor, and structural studies reveal a novel mode of ubiquitin recognition. Rpn13 is also a receptor for a deubiquitinating enzyme, suggesting a linkage between ubiquitin chain recognition and disassembly.

Ubiquitin chains have critical roles in activating the NF-κB pathway and mediating immune responses. Recent structural work on distinct ubiquitin chains in complexes with selective ubiquitin-binding domains provides an explanation for directionality and specificity in the NF-κB pathway.

A protein in the pathogenic bacterium Legionella pneumophila has been found to attach the modifying molecule ubiquitin to human proteins, using a mechanism that, surprisingly, does not involve cellular E1 and E2 enzymes. See Letter p.120

The degradation of dysfunctional proteins and organelles by autophagy is important for cell viability. Dikic and co-authors discuss how cargo selection is achieved during selective autophagy and how the processes involved in cargo delivery are related to membrane trafficking pathways.

Deubiquitinase OTULIN targets linear (M1-linked) ubiquitin chain patches on cytosolic Salmonella Typhimurium to modulate NEMO, IKKα/IKKβ and NF-ĸB signalling and regulate secretion of pro-inflammatory cytokines and bacterial proliferation.

The HECT-like E3 ligase SopA inSalmonellahas been suggested to activate host RING ligases TRIM56 and TRIM65. Here, the authors use mass spectrometry, crystal structures and biochemistry to examine the interactions between these proteins in detail.

Ubiquitin and ubiquitin-like proteins (Ubls) participate in many cellular processes, such as apoptosis and DNA repair. How can the deregulation of ubiquitin and Ubls lead to cancer formation, and how might ubiquitin and Ubl pathways be targeted by anticancer therapeutics?

Biotinylated tags bind double-strand breaks in genomic DNA; after enrichment and sequencing, this allows precise, genome-wide mapping of the breaks.

The 26S proteasome is a multisubunit complex that selectively degrades ubiquitin conjugated proteins. Two studies (this Article and the Letter Dikic doi:10.1038/nature06924) show that a known component of the proteasome, Rpn13, functions as a novel ubiquitin binding receptor, and structural studies reveal a novel mode of ubiquitin recognition. Rpn13 is also a receptor for a deubiquitinating enzyme, suggesting a linkage between ubiquitin chain recognition and disassembly.

Recent studies have revealed a prominent role of mitochondrial dysfunction in the development of one of the most common neurodegenerative disorders, Parkinson's disease. The ubiquitin ligase Parkin and the protein kinase PINK1, whose mutations are associated with Parkinson's disease, function in a pathway that links ubiquitylation with selective autophagy of damaged mitochondria.

The RING protein RBX-1 is implicated in both NEDDylation and ubiquitylation reactions. In this issue, new structural analysis reveals how conformational flexibility of the RBX-1 linker allows for a marked reorientation of the CUL1–RBX1 complex to facilitate transfer of NEDD8 or ubiquitin by closing the gap between the E2 catalytic site and the substrate.

In the ubiquitin network, a multitude of ubiquitin species is constantly decoded by ubiquitin-binding domains. To properly coordinate biological events, ubiquitylation depends on strict spatiotemporal regulation, which is achieved by compartmentalization, sequential series of ubiquitylation events and crosstalk with other post-translational modifications.

Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the protein modifier ubiquitin. Recent structures of ubiquitin–UBD complexes at atomic-level resolution reveal some of the mechanisms that underlie the versatile functions of ubiquitinin vivo.

PINK1 and parkin proteins help to degrade damaged mitochondrial organelles, and abnormalities in these proteins are linked to Parkinson’s disease. Mouse studies reveal that the proteins act to prevent inflammation.

Ubiquitin, best known as a degradation signal, is also a protein-sorting tag on endocytic cargoes and a regulatory switch on endocytic adaptor proteins. Parkin, a ubiquitin ligase whose mutations are associated with Parkinson's disease, has now been shown to control EGF-receptor internalization and Akt signalling by ubiquitination of the endocytic scaffold protein Eps15.

Structural and functional investigations demonstrate how bacterial enzymes ubiquitinate host proteins.

The secreted factor EGFL7, which is known to regulate cell migration and angiogenesis, is expressed in the brain where it binds receptors of the Notch family. Binding decreases Notch signalling, inhibits self-renewal of neural stem cells in culture and affects proliferation and differentiation of adult neural stem cells.

Autophagy is a process of cellular self-consumption that promotes cell survival in response to stress. Various human pathologies, including cancer, neurodegeneration and inflammation, have been associated with aberrant autophagy, and recent studies of the mechanisms and regulation of autophagy in higher eukaryotes have suggested new therapeutic possibilities.

Proteins are controlled by post-translational modifications that can be recognized by specific protein-interaction domains. These domains read the state of the proteome and therefore couple post-translational modifications to cellular organization. But how domodification-dependent interactionssynergize to regulate cell behaviour?