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Paper Reading 01 Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma Stefanie N. Meyer, Claudio Scuoppo, Sofija Vlasevska, et al. 2019,Immunity51, 535–547 Diffuse large B cell lymphoma(DLBCL) and follicular lymphoma (FL) are the most common lymphoid malignancies, together accounting for ~60% of B cell lymphoma diagnoses. Despite the significant progress made in the therapeutic management of these diseases, both remain partially unmet clinical needs. In particular, substantial fractions of DLBCL patients do not achieve complete remission with current first-line chemo-immunotherapeutic approaches and FL, although indolent, is essentially incurable. Moreover, as many as 45% of FL cases transform into a high-grade malignancy, typically a DLBCL (also known as transformed FL or tFL), with dismal overall survival. The development of treatments that can eradicate the reservoir of initiating cells responsible for resistance and transformation remains a high priority in the field. Over the past decade, genomic analysis of FL and DLBCL have uncovered highly recurrent somatic mutations and deletions in the histone acetyl-transferase gene CREBBP (60% of FL and 25% of DLBCL), with its paralogue EP300 being targeted at much lower frequencies (5% of FL and DLBCL). CREBBP and EP300 encode for ubiquitously expressed mammalian enzymes that act as global transcriptional co-activators by interacting with more than 400 transcription factors and by catalyzing the modification of lysines on both histone and non-histone proteins in a cell-context-dependent manner. Genetic alterations of CREBBP and EP300 are largely non-overlapping in FL and in DLBCL. Here, the authors used mouse models where Ep300 and/or Crebbp were specifically deleted in GC B cells to explore the relationship between CREBBP and EP300 in GC physiology and lymphomagenesis. They found that these two enzymes have common as well as distinct transcriptional targets in sub-compartments of the GC reaction, whereas their combined genetic deletion abrogated GC formation in vivo and impaired DLBCL cell line growth, suggesting that CREBBP-mutant DLBCL might depend on the residual EP300 activity. Treatment with small molecule inhibitors of CREBBP and EP300 was preferentially toxic toCREBBP- mutant DLBCL, establishing a paralogue lethality that could be explored as an actionable therapeutic target. https:///10.1016/j.immuni.2019.08.006 02 OTUD4 is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling Yu Zhao, Miranda C. Mudge, Jennifer M. Soll, et al. 2018, Molecular Cell 69, 505–516 Ubiquitin is an abundant small polypeptide found in all eukaryotes. How specific substrates are targeted for ubiquitination and which ubiquitin linkage is used for a given substrate are critical questions that are only partially answered. The vast number of E3 ubiquitin ligases (>300 in the human genome), which function by direct interaction with individual targets, likely provides much of the specificity for substrate selection. Regulation of deubiquitinases (DUBs) by accessory domains or additional post-translational modifications has emerged as an important mechanism by which ubiquitin signaling is controlled. Several OTU DUBfamily members, such as OTUD1 and TRABID, containing ubiquitin-binding domains(UBDs) that promote selectivity toward K63-linked and K29/K33-linked ubiquitin chains, respectively. On the other hand, OTUD2 is a relatively non-selective DUB, but this broad activity requires its zinc-finger domain. Certain DUBs have also been shown to become activated by post-translational modifications, including OTUD5/DUBA, A20, and OTUB1. However, how these modifications alter the linkage specificity and function of these DUBs in vivo, or how they may cooperate with UBDs, is only starting to be understood. In this study, they show that OTUD4,a K48-specific DUB which we previously showed to be important for maintaining the stability of alkylation repair enzymes, has a completely distinct function in modulating innate immune signaling via NF-kB. They find that OTUD4 is phosphorylated in vivo, activating an unrecognized K63-linked DUB activity. This activity relies not only on its phosphorylation but also on a UBD adjacent to its OTU catalytic domain. OTUD4directly recognizes and deubiquitinates MyD88 to inhibit NF-kB signaling. This mechanism provides functional flexibility to OTUD4 and establishes MyD88K63-linked deubiquitination as an additional node for canonical NF-kB regulation. https:///10.1016/j.molcel.2018.01.009 END |
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