Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD.

Bacterial Subversion Tactics: Intracellular bacterial pathogens such asListeria monocytogenescan change host cell transcription programs to promote infection.Eskandarianet al.(1238858) found that during infection, theListeriaeffector protein InlB promoted the movement of a host protein deacetylase, SIRT2, from its normal location in the cytosol to the nucleus. In the nucleus, SIRT2 helped to repress a number of host cell genes by deacetylating one of their associated histones. In mice, reduced levels of SIRT2 impaired bacterial infection.

Significance: Small ubiquitin-related modifier (SUMO) is a posttranslational modification essential for many functions in eukaryotic cells. A better understanding of the role of this ubiquitin-like modification, identification of proteins modified by SUMO, and knowledge of the exact sites of SUMO conjugation are critical but remain experimentally challenging. We have developed an innovative proteomic strategy allowing proteome-wide identification of SUMOylation sites and quantification of cell SUMOylation changes in response to diverse stimuli. Identification of yet unknown SUMO targets and characterization of SUMOylome alterations in response to environmental stresses, drugs, toxins, or bacterial and viral infections will help decipher previously unidentified roles of SUMOylation in cell physiology and disease.