TRIMming down to TRIM37: Relevance to Inflammation, Cardiovascular Disorders, and Cancer in MULIBREY Nanism

TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the MULIBREY (MUscle-LIver-BRain-EYe) genetic disorder caused by TRIM37 mutations. TRIM37 is characterized by the presence of a RING domain, B-box motifs, and a coiled-coil region, and its C-terminal part includes the MATH domain specific to TRIM37. MULIBREY nanism is a rare autosomal recessive caused by TRIM37 mutations and characterized by severe pre- and postnatal growth failure. Constrictive pericarditis is the most serious anomaly of the disease and is present in about 20% of patients. The patients have a deregulation of glucose and lipid metabolism, including type 2 diabetes, fatty liver, and hypertension. Puzzlingly, MULIBREY patients, deficient for TRIM37, are plagued with numerous tumors. Among non-MULIBREY patients affected by cancer, a wide variety of cancers are associated with an overexpression of TRIM37. This suggests that normal cells need an optimal equilibrium in TRIM37 expression. Finding a way to keep that balance could lead to potential innovative drugs for MULIBREY nanism, including heart condition and carcinogenesis treatment.

Download Full-text

Functional interactions between ubiquitin E2 enzymes and TRIM proteins

Biochemical Journal ◽

10.1042/bj20101487 ◽

2011 ◽

Vol 434 (2) ◽

pp. 309-319 ◽

Cited By ~ 71

Author(s):

Luisa M. Napolitano ◽

Ellis G. Jaffray ◽

Ronald T. Hay ◽

Germana Meroni

Keyword(s):

Coiled Coil ◽

Specific Interactions ◽

E3 Ligases ◽

Cellular Processes ◽

Coiled Coil Region ◽

Physiological Relevance ◽

Tripartite Motif ◽

E2 Enzymes ◽

Specific Reactions ◽

Trim Proteins

The TRIM (tripartite motif) family of proteins is characterized by the presence of the tripartite motif module, composed of a RING domain, one or two B-box domains and a coiled-coil region. TRIM proteins are involved in many cellular processes and represent the largest subfamily of RING-containing putative ubiquitin E3 ligases. Whereas their role as E3 ubiquitin ligases has been presumed, and in several cases established, little is known about their specific interactions with the ubiquitin-conjugating E2 enzymes or UBE2s. In the present paper, we report a thorough screening of interactions between the TRIM and UBE2 families. We found a general preference of the TRIM proteins for the D and E classes of UBE2 enzymes, but we also revealed very specific interactions between TRIM9 and UBE2G2, and TRIM32 and UBE2V1/2. Furthermore, we demonstrated that the TRIM E3 activity is only manifest with the UBE2 with which they interact. For most specific interactions, we could also observe subcellular co-localization of the TRIM involved and its cognate UBE2 enzyme, suggesting that the specific selection of TRIM–UBE2 pairs has physiological relevance. Our findings represent the basis for future studies on the specific reactions catalysed by the TRIM E3 ligases to determine the fate of their targets.

Download Full-text

Weight Growth Velocity and Postnatal Growth Failure in Infants 501 to 1500 Grams: 2000-2013

PEDIATRICS ◽

10.1542/peds.2015-0129 ◽

2015 ◽

Vol 136 (1) ◽

pp. e84-e92 ◽

Cited By ~ 134

Author(s):

J. D. Horbar ◽

R. A. Ehrenkranz ◽

G. J. Badger ◽

E. M. Edwards ◽

K. A. Morrow ◽

...

Keyword(s):

Growth Velocity ◽

Growth Failure ◽

Postnatal Growth ◽

Weight Growth ◽

Postnatal Growth Failure

Download Full-text

0897 Sleep Disordered Breathing In Pediatric Patients With Turner Syndrome

SLEEP ◽

10.1093/sleep/zsaa056.893 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A341-A342

Author(s):

Y A Yu ◽

B V Vaughn

Keyword(s):

Sleep Apnea ◽

Turner Syndrome ◽

Sleep Disordered Breathing ◽

Pediatric Patients ◽

Genetic Disorder ◽

Case Series ◽

Growth Failure ◽

Retrospective Chart Review ◽

Upper Airway Resistance Syndrome ◽

Disordered Breathing

Abstract Introduction Turner syndrome (TS) is a common genetic disorder that affects phenotypic females with partial or complete absence of one X chromosome. It typically presents with characteristic facial appearance, neck webbing, lymphedema, linear growth failure, and ovarian insufficiency. TS is also associated with other disorders, though sleep related disorders are not commonly reported. We present a case series of pediatric patients diagnosed with TS and assess their risk for sleep disordered breathing. Methods This study utilized retrospective chart review of the electronic medical record at the University of North Carolina at Chapel Hill from April 2014 to January 2019. Only pediatric patients under the age of 18 years who had previously undergone polysomnography and carrying the diagnosis of Turner syndrome were included in this study. Polysomnography results were reviewed. Results Retrospective chart analysis yielded ten (10) patients who qualified for inclusion. The mean age was 8.3 years (age range 1-15 years). Nine (9) patients were found to have sleep disordered breathing ranging from upper airway resistance syndrome to moderate sleep apnea (AHI range 1.2 to 6.2). Six (6) patients were found to have elevated periodic limb movement indices (PLM index range 5.1 to 30). Parasomnias and hypoventilation were not seen. Conclusion Our case series illustrates that sleep disordered breathing may be more common in TS than previously realized. Eklund et al. found that females with TS had more retrognathic mandibles and maxillas, shorter mandibles, and larger cranial base angles. These findings may indicate elevated risk of sleep apnea. Further studies are needed to define the overall risk of sleep disordered breathing in TS. Support None.

Download Full-text

Aortic growth arrest after preterm birth: a lasting structural change of the vascular tree

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174411000274 ◽

2011 ◽

Vol 2 (4) ◽

pp. 218-225 ◽

Cited By ~ 18

Author(s):

U. Schubert ◽

M. Müller ◽

A.-K. Edstedt Bonamy ◽

H. Abdul-Khaliq ◽

M. Norman

Keyword(s):

Preterm Birth ◽

Carotid Artery ◽

Preterm Infants ◽

Growth Failure ◽

Later Life ◽

Postnatal Growth ◽

Direct Result ◽

Arterial Tree ◽

Very Preterm Infants ◽

Very Preterm

Young people who are born very preterm exhibit a narrower arterial tree as compared with people born at term. We hypothesized that such arterial narrowing occurs as a direct result of premature birth. The aim of this study was to compare aortic and carotid artery growth in infants born preterm and at term. Observational and longitudinal cohort study of 50 infants (21 born very preterm, all appropriate for gestational age, 29 controls born at term) was conducted. Diameters of the upper abdominal aorta and common carotid artery were measured with ultrasonography at three months before term, at term and three months after term-equivalent age. At the first assessment, the aortic end-diastolic diameter (aEDD) was slightly larger in very preterm infants as compared with fetal dimensions. Fetal aortic EDD increased by 2.6 mm during the third trimester, whereas very preterm infants exhibited 0.9 mm increase in aEDD during the same developmental period (P < 0.001 for group difference). During the following 3-month period, aortic growth continued unchanged (+0.9 mm) in very preterm infants, whereas postnatal growth in term controls slowed down to +1.3 mm (P < 0.001 v. fetal aortic growth). At the final examination, aEDD was 22% and carotid artery EDD was 14% narrower in infants born preterm compared with controls, also after adjusting for current weight (P < 0.01). Aortic and carotid artery growth is impaired after very preterm birth, resulting in arterial narrowing. Arterial growth failure may be a generalized vascular phenomenon after preterm birth, with implications for cardiovascular morbidity in later life.

Download Full-text

A Coiled-Coil Domain of Melanophilin Is Essential for Myosin Va Recruitment and Melanosome Transport in Melanocytes

Molecular Biology of the Cell ◽

10.1091/mbc.e06-05-0457 ◽

2006 ◽

Vol 17 (11) ◽

pp. 4720-4735 ◽

Cited By ~ 61

Author(s):

Alistair N. Hume ◽

Abul K. Tarafder ◽

José S. Ramalho ◽

Elena V. Sviderskaya ◽

Miguel C. Seabra

Keyword(s):

Coiled Coil ◽

Binding Domain ◽

Actin Binding ◽

Binding Studies ◽

Null Cell ◽

Coiled Coil Region ◽

Actin Binding Domain ◽

Transport Assay ◽

Myosin Va

Melanophilin (Mlph) regulates retention of melanosomes at the peripheral actin cytoskeleton of melanocytes, a process essential for normal mammalian pigmentation. Mlph is proposed to be a modular protein binding the melanosome-associated protein Rab27a, Myosin Va (MyoVa), actin, and microtubule end-binding protein (EB1), via distinct N-terminal Rab27a-binding domain (R27BD), medial MyoVa-binding domain (MBD), and C-terminal actin-binding domain (ABD), respectively. We developed a novel melanosome transport assay using a Mlph-null cell line to study formation of the active Rab27a:Mlph:MyoVa complex. Recruitment of MyoVa to melanosomes correlated with rescue of melanosome transport and required intact R27BD together with MBD exon F–binding region (EFBD) and unexpectedly a potential coiled-coil forming sequence within ABD. In vitro binding studies indicate that the coiled-coil region enhances binding of MyoVa by Mlph MBD. Other regions of Mlph reported to interact with MyoVa globular tail, actin, or EB1 are not essential for melanosome transport rescue. The strict correlation between melanosomal MyoVa recruitment and rescue of melanosome distribution suggests that stable interaction with Mlph and MyoVa activation are nondissociable events. Our results highlight the importance of the coiled-coil region together with R27BD and EFBD regions of Mlph in the formation of the active melanosomal Rab27a-Mlph-MyoVa complex.

Download Full-text