Co-chairs Claudio Joazeiro (The Scripps Research Institute) and Frauke Melchior (University of Heidelberg) put together a minisymposium on the third day of ASCB 2011 that nicely highlighted the diversity of cellular functions performed by ubiquitin and ubiquitin-like proteins.
Ubiquitin is best known for its role in protein degradation when E3 ubiquitin ligases tag proteins with ubiquitin in order to target them to the proteasome. But, as Joazeiro described in his opening talk, individual E3 ligases can take part in very specific degradation pathways, a fact exemplified by Listerin, an E3 ligase whose mutation in mice causes motor neuron degeneration. Joazeiro showed that the yeast homolog of Listerin, Ltn1, is involved in a type of protein degradation linked to an mRNA quality control pathway called non-stop mRNA decay. This pathway rids cells of mRNAs that lack a proper stop codon, but an abnormal polypeptide is always produced before the mRNA can be eliminated. Joazeiro showed that Ltn1 associates with ribosomes and targets for destruction the proteins produced from non-stop mRNAs.
Probably the second-best known role for ubiquitination is in cell signaling. Fumiyo Ikeda (IMBA, Vienna) presented data from her recent paper describing how SHARPIN - a component of the Linear Ubiquitin Chain Assembly Complex (LUBAC) - regulates two signaling pathways. SHARPIN promotes NFkappaB signaling by mediating the ubiquitination of and NFkappaB regulator called NEMO, and it also inhibits cell death by restricting apoptotic signaling through the death domain-containing protein FADD. SHARPIN-deficient mice therefore suffer from increased apoptosis and inflammation.
The following two talks dealt with some less-appreciated roles of ubiquitination. Corinne Albiges-Rizo (Institut Albert Bonniot, Grenoble) discussed how ubiquitination of an integrin-binding protein helps regulate cell adhesion and migration. And Yanzhuang Wang (University of Michigan) described how the E3 ubiquitin ligase HACE1 is required for the reassembly of the Golgi apparatus after mitosis. (Interestingly, HACE1 is a tumor suppressor. Is there a connection between a failure to reassemble the Golgi and tumorigenesis?)
The final two talks examined the cellular functions of ubiquitin-like molecules. Jay Debnath (UC San Francisco) spoke about Atg12, a ubiquitin-like modifier required for expanding autophagosomal membranes during macroautophagy. Debnath and colleagues found that Atg12 can be conjugated to Atg3, a protein involved in the conjugation of another ubiquitin-like protein, LC3, that is also required for autophagy. The Atg12-Atg3 conjugate isn't required for starvation-induced autophagy, however. Instead, preventing the formation of Atg12-Atg3 conjugates blocks the related pathway of mitophagy (in which mitochondria are degraded) and also inhibits mitochondrial fusion, resulting in cells with increased numbers of highly-fragmented mitochondria. Debnath thinks that Atg12 may be conjugated to several other proteins and have important functions in a number of other cellular pathways as well.
And session co-chair Frauke Melchior finished off the session with a presentation on how oxidative stress regulates the small, ubiquitin-like modifier SUMO. Sumoylation is a reversible post-translational modification that affects the function of many different proteins. Reactive oxygen species cause a reduction in the sumoylation of many target proteins. In 2006, Melchior published that ROS inhibit sumoylation by promoting the formation of a disulphide bond between catalytic cysteine residues in two enzymes required for sumoylation, blocking the activity of both proteins. Melchior now described some follow up experiments to this initial report, looking at the potential functional consequences to cells if oxidative stress fails to shut down sumoylation.