45 research outputs found
Structure and catalytic regulatory function of ubiquitin specific protease 11 N-terminal and ubiquitin-like domains
The ubiquitin specific protease 11 (USP11) is implicated in DNA repair, viral RNA replication, and TGFβ signaling. We report the first characterization of the USP11 domain architecture and its role in regulating the enzymatic activity. USP11 consists of an N-terminal "domain present in USPs" (DUSP) and "ubiquitin-like" (UBL) domain, together referred to as DU domains, and the catalytic domain harboring a second UBL domain. Crystal structures of the DU domains show a tandem arrangement with a shortened β-hairpin at the two-domain interface and altered surface characteristics compared to the homologues USP4 and USP15. A conserved VEVY motif is a signature feature at the two-domain interface that shapes a potential protein interaction site. Small angle X-ray scattering and gel filtration experiments are consistent with the USP11DU domains and full-length USP11 being monomeric. Unexpectedly, we reveal, through kinetic assays of a series of deletion mutants, that the catalytic activity of USP11 is not regulated through intramolecular autoinhibition or activation by the N-terminal DU or UBL domains. Moreover, ubiquitin chain cleavage assays with all eight linkages reveal a preference for Lys(63)-, Lys(6)-, Lys(33)-, and Lys(11)-linked chains over Lys(27)-, Lys(29)-, and Lys(48)-linked and linear chains consistent with USP11's function in DNA repair pathways that is mediated by the protease domain. Our data support a model whereby USP11 domains outside the catalytic core domain serve as protein interaction or trafficking modules rather than a direct regulatory function of the proteolytic activity. This highlights the diversity of USPs in substrate recognition and regulation of ubiquitin deconjugation
A genome-wide association study of marginal zone lymphoma shows association to the HLA region
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility
PTMs in Conversation: Activity and Function of Deubiquitinating Enzymes Regulated via Post-Translational Modifications
Deubiquitinating enzymes (DUBs) constitute a diverse protein family and their impact on numerous biological and pathological processes has now been widely appreciated. Many DUB functions have to be tightly controlled within the cell, and this can be achieved in several ways, such as substrate-induced conformational changes, binding to adaptor proteins, proteolytic cleavage, and post-translational modifications (PTMs). This review is focused on the role of PTMs including monoubiquitination, sumoylation, acetylation, and phosphorylation as characterized and putative regulative factors of DUB function. Although this aspect of DUB functionality has not been yet thoroughly studied, PTMs represent a versatile and reversible method of controlling the role of DUBs in biological processes. In several cases PTMs might constitute a feedback mechanism insuring proper functioning of the ubiquitin proteasome system and other DUB-related pathways
Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia
Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy
Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture
Athletic injuries of the extensor carpi ulnaris subsheath: MRI findings and utility of gadolinium-enhanced fat-saturated T1-weighted sequences with wrist pronation and supination
Purpose: To report the magnetic resonance imaging (MRI) findings in athletic
injuries of the extensor carpi ulnaris (ECU) subsheath, assessing the utility of
gadolinium-enhanced (Gd) fat-saturated (FS) T1-weighted sequences with wrist
pronation and supination.
Methods and Materials: Sixteen patients (13 males, 3 females; mean age 30.3
years) with athletic injuries of the ECU subsheath sustained between January 2003
and June 2009 were included in this retrospective study. Initial and follow‑up 1.5-T
wrist MRIs were performed with transverse T1-weighted and STIR sequences in
pronation, and Gd FS T1-weighted sequences with wrist pronation and supination.
Two radiologists assessed the type of injury (A to C), ECU tendon stability,
associated lesions and rated pulse sequences using a three-point scale: 1 = poor,
2 = good and 3 = excellent.
Results: Gd-enhanced FS T1-weighted transverse sequences in supination (2.63)
and pronation (2.56) were most valuable, compared with STIR (2.19) and T1
weighted (1.94). Nine type A, one type B and six type C injuries were found. There
were trends towards diminution in size, signal intensity and enhancement of associated
pouches on follow‑up MRI and tendon stabilisation within the ulnar groove.
Conclusion: Gd-enhanced FS T1-weighted sequences with wrist pronation and
supination are most valuable in assessing and follow‑up athletic injuries of the
ECU subsheath on 1.5-T MRI
Extensor carpi ulnaris injuries in tennis players: a study of 28 cases
Pain on the ulnar side of the wrist is common among elite tennis players. Ten years of experience has allowed identification of a pathology involving the extensor carpi ulnaris (ECU) tendon. On the basis of 28 clinical cases seen over the last five years, three clinical patterns are described: (a) acute instability of the ECU; (b) tendinopathy; (c) ECU rupture. Each of these clinical entities requires a different therapeutic approach. A review of the relevant anatomy is provided
Extensor carpi ulnaris (ECU) subsheath: Normal MRI appearance and findings in athletic injuries : 40
Purpose: First, to report ECU subsheath's normal MRI appearance
and the findings in athletic injuries. Second, to determine the best MRI
sequence for diagnosis.
Methods and materials: Sixteen patients (13 males, 3 females, mean
age 30.3 years) with ECU subsheath's athletic injuries sustained
between January 2003 and June 2009 were retrospectively reviewed.
Wrist MRI studies were performed on 1.5-T units and consisted of at
least transverse T1 and STIR sequences in pronation, and FS Gd T1
in pronation and supination. Two radiologists assessed the following
items, in consensus: injury type (A to C according to Inoue), ECU
tendon stability, and associated lesions (ulnar head oedema, extensor
retinaculum injury, ECU tendinosis and tenosynovitis). Then, each
reader independently rated the sequences' diagnostic value:
0 = questionable, 1 = suggestive, 2 = certain. Follow-up studies were
present in 8 patients. ECU subsheath's normal visibility (medial, central
and lateral parts) was retrospectively evaluated in 30 consecutive
control MRI studies.
Results: FS Gd T1 sequences in supination (1.63) and pronation (1.59)
were the most valuable for diagnosis, compared to STIR (1.22) and T1
(1). The study group included 9 type A, 1 type B and 6 type C injuries.
There were trends towards diminution in pouches' size, signal intensity
and enhancement in follow-up studies, along with tendon stabilization
within the ulnar groove. In control studies, ECU subsheath's visibility in
medial, central and lateral parts were noted in 66.7-80%, 63.3-80%
and 30-50% respectively.
Conclusion: ECU subsheath's athletic injuries are visible on 1.5-T MRI
studies. FS Gd T1 sequences in supination and pronation are the most
valuable