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Paper Reading01
Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases inGerminal 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 commonlymphoid malignancies, together accounting for ~60% of B cell lymphoma diagnoses. Despitethe significant progress made in the therapeutic management of these diseases, both remainpartially unmet clinical needs. In particular, substantial fractions of DLBCL patients do not
achieve complete remission with current first-line chemo-immunotherapeutic approaches andFL, 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 ortFL), with dismal overall survival. The development of treatments that can eradicate thereservoir of initiating cells responsible for resistance and transformation remains a highpriority in the field.
Over the past decade, genomic analysis of FL and DLBCL have uncovered highly recurrentsomatic mutations and deletions in the histone acetyl-transferase gene CREBBP (60% of FLand 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 400transcription 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 deletedin GC B cells to explore the relationship between CREBBP and EP300 in GC physiology andlymphomagenesis. They found that these two enzymes have common as well as distincttranscriptional targets in sub-compartments of the GC reaction, whereas their combinedgenetic 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 toxictoCREBBP- mutant DLBCL, establishing a paralogue lethality that could be explored as anactionable therapeutic target.
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 substratesare targeted for ubiquitination and which ubiquitin linkage is used for a given substrate arecritical 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, likelyprovides much of the specificity for substrate selection. Regulation of deubiquitinases (DUBs)by accessory domains or additional post-translational modifications has emerged as animportant mechanism by which ubiquitin signaling is controlled. Several OTU DUBfamilymembers, such as OTUD1 and TRABID, containing ubiquitin-binding domains(UBDs) thatpromote 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 itszinc-finger domain. Certain DUBs have also been shown to become activated by post-translational modifications, including OTUD5/DUBA, A20, and OTUB1. However, how thesemodifications alter the linkage specificity and function of these DUBs in vivo, or how theymay 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 beimportant for maintaining the stability of alkylation repair enzymes, has a completely distinctfunction 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 reliesnot 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. Thismechanism provides functional flexibility to OTUD4 and establishes MyD88K63-linkeddeubiquitination as an additional node for canonical NF-kB regulation.
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