We summarize the evolutionary relationship, structure and subcellular distribution of SUMO proteases (or SUMO isopeptidases). We also discuss their functions and allude to their involvement in human disease.

The family of NFAT (nuclear factor of activated T-cells) transcription factors plays an important role in cytokine gene regulation. In peripheral T-cells NFATc1 and -c2 are predominantly expressed. Because of different promoter and poly(A) site usage as well as alternative splicing events, NFATc1 is synthesized in multiple isoforms. The highly inducible NFATc1/A contains a relatively short C terminus, whereas the longer, constitutively expressed isoform NFATc1/C spans an extra C-terminal peptide of 246 amino acids. Interestingly, this NFATc1/C-specific terminus can be highly sumoylated. Upon sumoylation, NFATc1/C, but not the unsumoylated NFATc1/A, translocates to promyelocytic leukemia nuclear bodies. This leads to interaction with histone deacetylases followed by deacetylation of histones, which in turn induces transcriptionally inactive chromatin. As a consequence, expression of the NFATc1 target gene interleukin-2 is suppressed. These findings demonstrate that the modification by SUMO (small ubiquitin-like modifier) converts NFATc1 from an activator to a site-specific transcriptional repressor, revealing a novel regulatory mechanism for NFATc1 function.

Tolerance to self-antigens expressed in peripheral organs is maintained by CD4 1 CD25 1 Foxp31 Treg cells, which are generated as a result of thymic selection or peripheral induction.Here, we demonstrate that steady-state migratory DCs from the skin mediated Treg conversion in draining lymph nodes of mice. These DCs displayed a partially mature MHC II int CD86 int CD40 hi CCR7 1 phenotype, used endogenous TGF-b for conversion and showed nuclear RelB translocation. Deficiency of the alternative NF-jB signaling pathway (RelB/p52) reduced steady-state migration of DCs. These DCs transported and directly presented soluble OVA provided by s.c. implanted osmotic minipumps, as well as cell-associated epidermal OVA in transgenic K5-mOVA mice to CD4 1 OVA-specific TCR-transgenic OT-II T cells. 1420antigens drained from peripheral tissues can be taken up from the fluid phase for presentation to T cells under steady-state conditions [4]. Recently, it has been reported that continuous peripheral antigen delivery can induce Treg conversion in draining lymph nodes. This suggests that the reticular conduit system delivers exogenous peptides under non-immunogenic conditions, which can be mimicked by implanted osmotic pumps, to lymph node-resident immature DCs, which then present these peptides to induce Tregs in vivo [5].Such mechanisms of antigen delivery may explain the induction of CD41 T-cell anergy as shown for antigen presentation by immature DCs expressing only low levels of MHC II and costimulatory molecules [6]. However, it does not explain how immature DCs may induce CD4 1 Treg since B7-1/B7-2 À/À and CD28 À/À mice lack CD4 1 CD25 1 Tregs despite the presence of immature DCs [7]. Splenic DCs converted Treg better than B cells, and CD80/86-deficiency of the DCs further increases the conversion. These conversion experiments were either in vitro studies or under a pathological situation (tumor) but not steady state [8]. Later, the splenic CD8a 1 DC subset was identified as mediating conversion after injection of a DEC205-targeting antibody [9]. The physiological relevance of splenic DCs or DEC205 for Treg conversion with self-antigens remains open. A CD103 1 DC population has been isolated from mesenteric lymph nodes that mediated TGF-b-dependent Treg conversion in culture, but the maturation stage of the DC has not been analyzed [10]. In contrast, a CD103 À DC subset within skin-draining lymph nodes was responsible for Treg conversion in vitro [11]. This indicates that CD103 expression by DCs is not correlated with their capacity to convert Tregs and a specific phenotype for DCs inducing Tregs under steady-state conditions and in vivo remains to be identified [12]. Fluid phase soluble antigen transport also does not explain how lymph node T cells can be tolerized against cell-associated antigens. Therefore, the presentation of self-antigens by migratory DCs has been suggested as a mechanism of peripheral tolerance since these cells can be observed in draining lymph nodes of various organs [13,14]. The mature CCR7-expre...

Autophagy is an intracellular recycling and degradation pathway that depends on membrane trafficking. Rab GTPases are central for autophagy but their regulation especially through the activity of Rab GEFs remains largely elusive. We employed a RNAi screen simultaneously monitoring different populations of autophagosomes and identified 34 out of 186 Rab GTPase, GAP and GEF family members as potential autophagy regulators, amongst them SMCR8. SMCR8 uses overlapping binding regions to associate with C9ORF72 or with a C9ORF72-ULK1 kinase complex holo-assembly, which function in maturation and formation of autophagosomes, respectively. While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2. Collectively, we established SMCR8 as multifaceted negative autophagy regulator.DOI: http://dx.doi.org/10.7554/eLife.23063.001

Cellular signaling pathways largely depend on the plasticity of multiprotein complexes. A central mechanism that assures the coordinated assembly and disassembly of protein complexes is the reversible post-translational modification of the individual components for example by phosphorylation, acetylation, or ubiquitylation. Accumulating evidence indicates that the small ubiquitin-related modifier (SUMO) system is another master organizer of protein complexes. Here, we will focus on the role of SUMO in the regulation of nuclear protein complexes that are involved in chromatin remodeling, double-strand break repair, and ribosome biogenesis. On the basis of these selected pathways, we will summarize current ideas of SUMO signaling, including the concept of group modification and the intersection of the ubiquitin and SUMO pathways.