α-/γ-Taxilin are required for centriolar subdistal appendage assembly and microtubule organization

Ma, Dandan; Wang, Fulin; Wang, Rongyi; Hu, Yingchun; Chen, Zhiquan; Tian, Yonglu; Xia, Yuqing; Jiang, Teng; Chen, Jianguo

doi:10.7554/elife.73252

Cited by 9 publications

(8 citation statements)

References 42 publications

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“…We speculate that taxilin family proteins have a similar ability to engage diverse sets of proteins through their CCD and IDPRs. While Txlnb is selectively expressed in striated muscle and has an unclear biological function, Txlna and Txlng are ubiquitously expressed across tissues, associate with centrosome and pericentriolar proteins 11,12 , bind to microtubules 54 , regulate protein trafficking 55 and influence the accumulation of UPS-targeted substrates 27 . Our results show that Txlnb increases UPS efficiency, though it remains unclear exactly how this occurs.…”

Section: Discussionmentioning

confidence: 99%

“…We stumbled upon the taxilin gene/protein family (Txlna, Txlnb, and Txlng) 10 that encodes centrosomal adapter proteins. 11,12 One member, Txlnb, is highly enriched in cardiomyocytes, but its roles in cardiac biology and disease remain understudied [13][14][15] . Notably, we found that Txlnb influences protein homeostasis in cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

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A Specialized Centrosome-Proteasome Axis Mediates Proteostasis and Influences Cardiac Stress through Txlnb

McLendon,

Zhang,

Stein

et al. 2024

Preprint

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BackgroundCentrosomes localize to perinuclear foci where they serve multifunctional roles, arranging the microtubule organizing center (MTOC) and anchoring ubiquitin-proteasome system (UPS) machinery. In mature cardiomyocytes, centrosomal proteins redistribute into a specialized perinuclear cage-like structure, and a potential centrosome-UPS interface has not been studied. Taxilin-beta (Txlnb), a cardiomyocyte-enriched protein, belongs to a family of centrosome adapter proteins implicated in protein quality control. We hypothesize that Txlnb plays a key role in centrosomal-proteasomal crosstalk in cardiomyocytes.MethodsIntegrative bioinformatics assessed centrosomal gene dysregulation in failing hearts. Txlnb gain/loss-of-function studies were conducted in cultured cardiomyocytes and mice. Txlnb’s role in cardiac proteotoxicity and hypertrophy was examined using CryAB-R120G mice and transverse aortic constriction (TAC), respectively. Molecular modeling investigated Txlnb structure/function.ResultsHuman failing hearts show consistent dysregulation of many centrosome-associated genes, alongside UPS-related genes. Txlnb emerged as a candidate regulator of cardiomyocyte proteostasis that localizes to the perinuclear centrosomal compartment. Txlnb’s interactome strongly supports its involvement in cytoskeletal, microtubule, and UPS processes, particularly centrosome-related functions. Overexpressing Txlnb in cardiomyocytes reduced ubiquitinated protein accumulation and enhanced proteasome activity during hypertrophy. Txlnb-knockout (KO) mouse hearts exhibit proteasomal insufficiency and altered cardiac growth, evidenced by ubiquitinated protein accumulation, decreased 26Sβ5 proteasome activity, and lower mass with age. In Cryab-R120G mice, Txlnb loss worsened heart failure, causing lower ejection fractions. After TAC, Txlnb-KO mice also showed reduced ejection fraction, increased heart mass, and elevated ubiquitinated protein accumulation. Investigations into the molecular mechanisms revealed that Txlnb-KO did not affect proteasomal subunit expression but led to the upregulation of Txlna and several centrosomal proteins (Cep63, Ofd1, and Tubg) suggesting altered centrosomal dynamics. Structural predictions support Txlnb’s role as a specialized centrosomal-adapter protein bridging centrosomes with proteasomes, confirmed by microtubule-dependent perinuclear localization.ConclusionsTogether, these data provide initial evidence connecting Txlnb to cardiac proteostasis, hinting at the potential importance of functional bridging between specialized centrosomes and UPS in cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Specialized Centrosome-Proteasome Axis Mediates Proteostasis and Influences Cardiac Stress through Txlnb

McLendon,

Zhang,

Stein

et al. 2024

Preprint

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“…Significant increases were also observed in proteins linked to cytoskeletal integrity and architecture. Striatin-interacting protein 2 (STRIP2) (0.58-log2FC; 1.49-FC) is involved in regulating cell morphology and cytoskeletal organization [46], protein 4.1 (EPB41) (0.23-log2FC; 1.18-FC) regulating spectrin-actin interaction contributing to cellular mechanical stability [47], and alpha-taxilin (TXLNA) (0.28-log2FC; 1.22-FC), involved in microtubule organization [48].…”

Section: Proteomic Analysis Of the Ecm Enriched Fraction Reveals The ...mentioning

confidence: 99%

Proteomic analysis uncovers clusterin-mediated disruption of actin-based contractile machinery in the trabecular meshwork to lower intraocular pressure

Soundararajan,

Wang,

Pattabiraman

2024

Preprint

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Glaucoma, a major cause of blindness, is characterized by elevated intraocular pressure (IOP) due to improper drainage of aqueous humor via the trabecular meshwork (TM) outflow pathway. Our recent work identified that loss of clusterin resulted in elevated IOP. This study delves deeper to elucidate the role of clusterin in IOP regulation. Employing an ex vivo human anterior segment perfusion model, we established that constitutive expression and secretion as well as exogenous addition of clusterin can significantly lower IOP. Interestingly, clusterin significantly lowered transforming growth factor β2 (TGFβ2)-induced IOP elevation. This effect was linked to the suppression of extracellular matrix (ECM) deposition and, highlighting the crucial role of clusterin in maintaining ECM equilibrium. A comprehensive global proteomic approach revealed the broad impact of clusterin on TM cell structure and function by identifying alterations in protein expression related to cytoskeletal organization, protein processing, and cellular mechanics, following clusterin induction. These findings underscore the beneficial modulation of TM cell structure and functionality by clusterin. Specifically, clusterin influences the actin-cytoskeleton and focal adhesion dynamics, which are instrumental in cell contractility and adhesion processes. Additionally, it suppresses the activity of proteins critical in TGFβ2, G-protein, and JAK-STAT signaling pathways, which are vital for the regulation of ocular pressure. By delineating these targeted effects of clusterin within the TM outflow pathway, our findings pave the way for novel treatment strategies aimed at mitigating the progression of ocular hypertension and glaucoma through targeted molecular interventions.

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“…Moreover γ-TXLN ablation may induce tau hyperphosphorylation in AD patients [ 131 ]. In the past few years, even if large body of evidence [ 132 , 133 ] supported physiological relevance of the taxilin family, further research on the role of family member γ-TXLN in neuropathology would be of great value.…”

Section: Human Nlrp2 Connectome With String Databasementioning

confidence: 99%

The Neglected Sibling: NLRP2 Inflammasome in the Nervous System

Ducza,

Gaál

2023

Aging and disease

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While classical NOD-like receptor pyrin domain containing protein 1 (NLRP1) and NLRP3 inflammasomal proteins have been extensively investigated, the contribution of NLRP2 is still ill-defined in the nervous system. Given the putative significance of NLRP2 in orchestrating neuroinflammation, further inquiry is needed to gain a better understanding of its connectome, hence its specific targeting may hold a promising therapeutic implication. Therefore, bioinformatical approach for extracting information, specifically in the context of neuropathologies, is also undoubtedly preferred. To the best of our knowledge, there is no review study selectively targeting only NLRP2. Increasing, but still fragmentary evidence should encourage researchers to thoroughly investigate this inflammasome in various animal- and human models. Taken together, herein we aimed to review the current literature focusing on the role of NLRP2 inflammasome in the nervous system and more importantly, we provide an algorithm-based protein network of human NLRP2 for elucidating potentially valuable molecular partnerships that can be the beginning of a new discourse and future therapeutic considerations.

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α-/γ-Taxilin are required for centriolar subdistal appendage assembly and microtubule organization

Cited by 9 publications

References 42 publications

A Specialized Centrosome-Proteasome Axis Mediates Proteostasis and Influences Cardiac Stress through Txlnb

A Specialized Centrosome-Proteasome Axis Mediates Proteostasis and Influences Cardiac Stress through Txlnb

Proteomic analysis uncovers clusterin-mediated disruption of actin-based contractile machinery in the trabecular meshwork to lower intraocular pressure

The Neglected Sibling: NLRP2 Inflammasome in the Nervous System

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