Met1-linked ubiquitin signalling in health and disease: inflammation, immunity, cancer, and beyond.

Post-translational modification of proteins with ubiquitin (ubiquitination) provides a rapid and versatile mechanism for regulating cellular signalling systems. Met1-linked (or 'linear') ubiquitin chains have emerged as a key regulatory signal that controls cell death, immune signalling, and other vital cellular functions. The molecular machinery that assembles, senses, and disassembles Met1-linked ubiquitin chains is highly specific. In recent years, the thorough biochemical and genetic characterisation of the enzymes and proteins of the Met1-linked ubiquitin signalling machinery has paved the way for substantial advances in our understanding of how Met1-linked ubiquitin chains control cell signalling and biology. Here, we review current knowledge and recent insights into the role of Met1-linked ubiquitin chains in cell signalling with an emphasis on their role in disease biology. Met1-linked ubiquitin has potent regulatory functions in immune signalling, NF-κB transcription factor activation, and cell death. Importantly, mounting evidence shows that dysregulation of Met1-linked ubiquitin signalling is associated with multiple human diseases, including immune disorders, cancer, and neurodegeneration. We discuss the latest evidence on the cellular function of Met1-linked ubiquitin in the context of its associated diseases and highlight new emerging roles of Met1-linked ubiquitin chains in cell signalling, including regulation of protein quality control and metabolism.

OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1.

Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [35S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses.

Extreme conservation and non-neutral evolution of the cpmA Circadian locus in a globally distributed Chroococcidiopsis sp. from naturally stressful habitats.

Cyanobacteria are among the most ancient organisms known to have circadian rhythms. The cpmA gene is involved in controlling the circadian output signal. We studied polymorphism and divergence of this gene in six populations of a stress-tolerant cyanobacterium, Chroococcidiopsis sp., sampled in extreme habitats across the globe. Despite high haplotype diversity (0.774), nucleotide diversity of cpmA is very low (π = 0.0034): the gene appears to be even more conserved than housekeeping genes. Even though the populations were sampled thousands kilometers apart, they manifested virtually no genetic differentiation at this locus (F(ST) = 0.0228). Using various tests for neutrality, we determined that evolution of cpmA significantly departures from the neutral model and is governed by episodic positive selection.