SoxD Proteins Influence Multiple Stages of Oligodendrocyte Development and Modulate SoxE Protein Function

SummaryThe myelin-forming oligodendrocytes are an excellent model to study transcriptional regulation of specification events, lineage progression, and terminal differentiation in the central nervous system. Here, we show that the group D Sox transcription factors Sox5 and Sox6 jointly and cell-autonomously regulate several stages of oligodendrocyte development in the mouse spinal cord. They repress specification and terminal differentiation and influence migration patterns. As a consequence, oligodendrocyte precursors and terminally differentiating oligodendrocytes appear precociously in spinal cords deficient for both Sox proteins. Sox5 and Sox6 have opposite functions than the group E Sox proteins Sox9 and Sox10, which promote oligodendrocyte specification and terminal differentiation. Both genetic as well as molecular evidence suggests that Sox5 and Sox6 directly interfere with the function of group E Sox proteins. Our studies reveal a complex regulatory network between different groups of Sox proteins that is essential for proper progression of oligodendrocyte development

A CARD10-dependent tonic signalosome activates MALT1 paracaspase and regulates IL-17/TNF-a driven keratinocyte inflammation

The paracaspase MALT1 (Mucosa associated lymphoid tissue lymphoma translocation protein 1) controls signaling downstream of several cell surface receptors, such as C-type lectin receptors on myeloid cells and antigen receptors on lymphocytes. Upon receptor engagement, MALT1, BCL10 (B-cell lymphoma/leukemia 10) and a CARD (Caspase recruitment domain) family member assemble into a ‘CBM’ complex, which is required to trigger MALT1 paracaspase activity and downstream transcriptional activation mechanisms (Meininger and Krappmann 2016; Rosebeck et al. 2011). Here, we found that CARD10 is highly expressed in proliferating keratinocytes and is responsible for a tonic level of paracaspase activity, driven by MALT1 isoform A. Furthermore, using the potent and selective MALT1 inhibitor MLT-827 (Bardet et al. 2018; Unterreiner et al. 2017), we reveal that MALT1 activity regulates pro-inflammatory responses downstream of IL-17/TNF-α

Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5

Cullin-RING ligases (CRLs) represent the largest family of E3 ubiquitin ligases. CSN5 is the zinc metalloprotease subunit of the COP9 signalosome, an important regulator of CRLs. Elevated expression of CSN5 has been found in several types of cancers. Altmann and coworkers describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion through an unprecedented binding mode. Nanomolar inhibitors led to degradation of the substrate recognition subunit Skp2 and reduced the viability of HCT116 cells. The study provides a proof-of-concept for the potential of CSN5 inhibitors as anticancer agents

Azaindoles as zinc-binding small molecule inhibitors of the JAMM protease CSN5

The COP9 signalosome (CSN) is an eight-subunit protein complex which is an important regulator of Cullin-Ring E3 ubiquitin ligases (CRLs). CSN5 is the Zinc metalloprotease subunit of CSN and is responsible for the cleavage of the ubiquitin-like protein NEDD8 from CRLs. Blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state leading to their inactivation by inducing auto-ubiquitination and subsequent degradation. Consequently CRL substrates (e.g. tumor suppressors p27 and p21) are stabilized resulting in inhibition of cell proliferation. Thus pharmacological inhibition of CSN5 has the potential to offer a new therapeutic strategy for an efficacious treatment of CSN5 dependent cancers. A high-throughput screen (HTS) with the entire CSN complex led to the identification of an azaindole hit as a micromolar CSN5 inhibitor. Optimization of this hit resulted in a series of potent CSN5 inhibitors which stabilized neddylated Cullin-1 and led to the degradation of Skp2 in HCT116 cells. Furthermore these inhibitors demonstrated the expected functional effect on inhibiting viability of cancer cells. In addition a X-ray cocrystal structure elucidated the binding mode and revealed the N7 of the azaindole as a monodate ligand of the active site Zn2+ ion. The 7-azaindole motif represents a novel Zinc-binding scaffold for metalloproteases

A first-in-class small molecule inhibitor of the COP9 signalosome subunit 5 for the treatment of cancer

The COP9 signalosome (CSN) is the platform for assembly and disassembly of cullin-RING E3 ubiquitin ligases (CRL), which comprise the largest enzyme family of the ubiquitin proteasome system (UPS) in humans1-4 . Over 200 CRL complexes are implicated in the regulation of almost all cellular processes including cell cycle progression, transcription, and apoptosis5, and aberrant CRL activity is frequently associated with cancer6-8. Since CSN functions as the protease which cleaves the ubiquitin-like protein Nedd8 from CRLs and thereby initiates their remodelling, inhibitors of the catalytic subunit CSN59 may have therapeutic potential for the treatment of tumours10,11. Here we present CSN5i- 3, a potent, selective and orally available small molecule inhibitor of CSN5. The compound traps CRLs in the neddylated, active state leading to the autoinactivation of a subset of CRLs, e.g. SCFSkp2, by inducing the degradation of their substrate recognition module (SRM). As a result, the corresponding CRL substrates are stabilized, e.g. tumour suppressors p21 and p27. Surprisingly, we also found CRLs, e.g. SCFβTrCP, whose SRMs are not degraded upon CSN5 inhibition, and their substrates remain unaffected. CSN5i-3 differentially affected tumour cell lines and suppressed growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has therapeutic potential for the treatment of cancer