scholarly journals Role of the Novel Hsp90 Co-Chaperones in Dynein Arms’ Preassembly

2019 ◽  
Vol 20 (24) ◽  
pp. 6174 ◽  
Author(s):  
Hanna Fabczak ◽  
Anna Osinka
Keyword(s):  
Crucial Role ◽  
Primary Cilia ◽  
Genetic Disorder ◽  
Complex Structures ◽  
The Novel ◽  
Heavy Chains ◽  
Dynein Arms ◽  
Human Genetic Disorder ◽  
Hsp 90

The outer and inner dynein arms (ODAs and IDAs) are composed of multiple subunits including dynein heavy chains possessing a motor domain. These complex structures are preassembled in the cytoplasm before being transported to the cilia. The molecular mechanism(s) controlling dynein arms’ preassembly is poorly understood. Recent evidence suggests that canonical R2TP complex, an Hsp-90 co-chaperone, in cooperation with dynein axonemal assembly factors (DNAAFs), plays a crucial role in the preassembly of ODAs and IDAs. Here, we have summarized recent data concerning the identification of novel chaperone complexes and their role in dynein arms’ preassembly and their association with primary cilia dyskinesia (PCD), a human genetic disorder.

Haunted Chinese Gay Identity

2018 ◽  
pp. 73-86
Author(s):  
Hongwei Bao
Keyword(s):  
Crucial Role ◽  
Gay Identity ◽  
The Novel ◽  
Social Critique ◽  
Subject Formation ◽  
Contemporary China ◽  
Potential Productivity ◽  
Chinese Context ◽  
Historical Memories

This chapter examines the construction of Chinese gay identity in a popular queer online fiction titled Beijing Story. Drawing on the Derridian notion of “hauntology”, I propose to read the novel as a social critique of postsocialist China in the context of globalization and neoliberalism. I highlight the intersections between sexuality, masculinity, and class in the narrative, and the potential productivity of paying more attention to the issue of class in queer subject formation in contemporary China. I also emphasize the crucial role of the transnational, as well as historical forms of homoeroticism and recent historical memories of revolution and reconstruction, in constructing contemporary gay identity in China. In doing so, I critically assess the role of “queer Marxism” (Liu 2015) in a transnational Chinese context.

scholarly journals A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability

2020 ◽  
Author(s):  
Abdelhalim Loukil ◽  
Chloe Barrington ◽  
Sarah C. Goetz
Keyword(s):  
Human Disease ◽  
Cellular Response ◽  
Primary Cilia ◽  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Super Resolution ◽  
Structural Defects ◽  
Mother Centriole ◽  
Human Genetic Disorder

ABSTRACTCilia biogenesis is a complex, multi-step process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified a kinase that acts as a key regulator of ciliogenesis, TTBK2. Here, using CRISPR kinome screening, we identify the CK2 subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Super-resolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages where it physically interacts with TTBK2. Further, Csnk2a1 knockout partially corrects defects in cilia formation and length in Ttbk2 hypomorphic cells. Csnk2a1 mutant cilia are longer than those of control cells and exhibit instability, particularly at the tip. Csnk2a1 mutant cilia also abnormally accumulate key cilia assembly and SHH-related proteins including IFT, GLI2, KIF7, and Smoothened (SMO). De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells cause ciliary structural defects. Our findings provide new insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance and implications of cilia instability in human disease.SIGNIFICANCE STATEMENTPrimary cilia (PC) are sensory organelles that play essential roles during development and adulthood. Abnormal functioning of PC causes human disorders called ciliopathies. Hence, a thorough understanding of the molecular regulation of PC is critical. Our findings highlight CSNK2A1 as a novel modulator of cilia trafficking and stability, tightly related to TTBK2 function. Enriched at the centrosome, CSNK2A1 prevents abnormal accumulation of key ciliary proteins, instability at the tip, and aberrant activation of the Sonic Hedgehog pathway. Further, we establish that Csnk2a1 mutations associated with Okur-Chung neurodevelopmental disorder (OCNDS) alter cilia morphology. Thus, we report a potential linkage between CSNK2A1 ciliary function and OCNDS.

Targeted Inactivation of the Mouse Locus Encoding Coagulation Factor XIII-A: Hemostatic Abnormalities in Mutant Mice and Characterization of the Coagulation Deficit

2002 ◽  
Vol 88 (12) ◽  
pp. 967-974 ◽  
Author(s):  
Peter Lauer ◽  
Hubert Metzner ◽  
Gerd Zettlmeißl ◽  
Meng Li ◽  
Austin Smith ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Factor Xiii ◽  
Genetic Disorder ◽  
Coagulation Factor ◽  
Mutant Mice ◽  
Targeted Deletion ◽  
Coagulation Factor Xiii ◽  
Tail Tip ◽  
Human Genetic Disorder

SummaryBlood coagulation factor XIII (FXIII) promotes cross-linking of fibrin during blood coagulation; impaired clot stabilization in human genetic deficiency is associated with marked pathologies of major clinical impact, including bleeding symptoms and deficient wound healing. To investigate the role of FXIII we employed homologous recombination to generate a targeted deletion of the inferred exon 7 of the FXIII-A gene. FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice. Plasma fibrin γ-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII. Homozygous mutant mice were fertile, although reproduction was impaired. Bleeding episodes, hematothorax, hematoperitoneum and subcutaneous hemorrhage in mutant mice were associated with reduced survival. Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin® P) restored bleeding time to within the normal range. Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization. The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies.

scholarly journals Regulation of Melanophilin (Mlph) gene expression by the glucocorticoid receptor (GR)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cheol Hwan Myung ◽  
Ji Eun Lee ◽  
Chan Song Jo ◽  
Jong il Park ◽  
Jae Sung Hwang
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Crucial Role ◽  
Transport Process ◽  
Skin Pigmentation ◽  
Transport Proteins ◽  
Immunofluorescence Staining ◽  
Binding Motif ◽  
The Novel

AbstractMlph plays a crucial role in regulating skin pigmentation through the melanosome transport process. Although Mlph is a major component involved in melanosome transport, the mechanism that regulates the expression of the Mlph gene has not been identified. In this study, we demonstrate that Mlph expression is regulated by the glucocorticoid receptor (GR). Alteration of GR activity using a specific GR agonist or antagonist only regulated the expression of Mlph among the 3 key melanosome transport proteins. Translocation of GR from the cytosol into the nucleus following Dex treatment was confirmed by separating the cytosol and nuclear fractions and by immunofluorescence staining. In ChIP assays, Dex induced GR binding to the Mlph promoter and we determined that Dex induced the GR binding motif on the Mlph promoter. Our findings contribute to understanding the regulation of Mlph expression and to the novel role of GR in Mlph gene expression.

scholarly journals Jacques Poulin’s Volkswagen Blues

2020 ◽  
Vol 35 (2) ◽  
pp. 269-280
Author(s):  
Fernando Sanz-Lázaro
Keyword(s):  
Crucial Role ◽  
Culturally Diverse ◽  
American Culture ◽  
The Novel ◽  
French Canadian ◽  
The Road ◽  
Anglo American ◽  
On The Road ◽  
Road Novel

This article analyses the intertextuality of the novel Volkswagen Blues by Jacques Poulin, a French-Canadian take on the road novel. The aim of the paper is to examine not only the relationships between Volkswagen Blues and its culturally diverse sources, but also to show how those multicultural intertexts permeate the road novel genre. In order to achieve this purpose, the study identifies in the novel instances of intertextuality which are analyzed within Genette’s framework for transtextuality. Considering the intertextual presence in Volkswagen Blues, the analysis ponders whether it is limited to this novel or is a manifestation of Americanness and, thus, a piece of evidence of multiculturality in the hegemonic American discourse. The study shows how Poulin depicts the crucial role of non-Anglo-American identities in contemporary American culture and explains the influence of world literatures in Poulin’s work

Role of molecular chaperones in steroid receptor action

2004 ◽  
Vol 40 ◽  
pp. 41-58 ◽  
Author(s):  
William B Pratt ◽  
Mario D Galigniana ◽  
Yoshihiro Morishima ◽  
Patrick J M Murphy
Keyword(s):  
Transcriptional Activation ◽  
Protein Trafficking ◽  
Steroid Receptors ◽  
Transcriptional Regulatory ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Receptor Action ◽  
Binding Cleft ◽  
Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

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