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pubmed: 1059-1524



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Spatial cues and not spindle pole maturation drive the asymmetry of astral microtubules between new and pre-existing spindle poles.

Spatial cues and not spindle pole maturation drive the asymmetry of astral microtubules between new and pre-existing spindle poles.

Mol Biol Cell. 2017 Nov 15;:

Authors: Lengefeld J, Yen E, Chen X, Leary A, Vogel J, Barral Y

Abstract
In many asymmetrically dividing cells, the microtubule-organizing centers (MTOCs; mammalian centrosome and yeast spindle pole body - SPB) nucleate more astral microtubules on one of the two spindle poles than the other. This differential activity generally correlates with the age of MTOCs and contributes to orienting the mitotic spindle within the cell. The asymmetry might results from the two MTOCs being in distinctive maturation states. We investigated this model in budding yeast. Using fluorophores with different maturation kinetics to label the outer plaque components of the SPB, we found that the Cnm67 protein is mobile, whereas Spc72 is not. However, these two proteins were rapidly as abundant on both SPBs, indicating that SPBs mature more rapidly than anticipated. Super-resolution microscopy confirmed this finding for Spc72 and for the γ-tubulin complex. Moreover, astral microtubule number and length correlated with the subcellular localization of SPBs rather than their age. Kar9-dependent orientation of the spindle drove the differential activity of the SPBs in astral microtubule organization, rather than intrinsic differences between the spindle poles. Together, our data establish that Kar9 and spatial cues rather than the kinetics of SPB maturation control the asymmetry of astral microtubule organization between the pre-existing and new SPBs.

PMID: 29142076 [PubMed - as supplied by publisher]




Cone myoid elongation involves unidirectional microtubule movement mediated by dynein-1.

Cone myoid elongation involves unidirectional microtubule movement mediated by dynein-1.

Mol Biol Cell. 2017 Nov 15;:

Authors: Lewis TR, Zareba M, Link BA, Besharse JC

Abstract
Teleosts and amphibians exhibit retinomotor movements, morphological changes in photoreceptors regulated by light and circadian rhythms. Cone myoid elongation occurs during dark adaptation leading to the positioning of the cone outer segment closer to the retinal pigment epithelium. While it has been shown that microtubules are essential for cone myoid elongation, the underlying mechanism has not been established. In this work, we generated a transgenic line of zebrafish expressing a photoconvertible form of α-tubulin (tdEOS-tubulin) specifically in cone photoreceptors. Using super-resolution structured illumination microscopy (SIM) in conjunction with both pharmacological and genetic manipulation, we show that cytoplasmic dynein-1, which localizes to the junction between the ellipsoid and myoid, functions to shuttle microtubules from the ellipsoid into the myoid during the course of myoid elongation. We propose a novel model by which stationary complexes of cytoplasmic dynein-1 are responsible for the shuttling of microtubules between the ellipsoid and myoid is the underlying force for the morphological change of myoid elongation.

PMID: 29142075 [PubMed - as supplied by publisher]




STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis post-transcriptionally and is essential for lung myofibroblast differentiation.

STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis post-transcriptionally and is essential for lung myofibroblast differentiation.

Mol Biol Cell. 2017 Nov 15;:

Authors: Papaioannou I, Xu S, Denton CP, Abraham DJ, Ponticos M

Abstract
Fibroblast differentiation is key cellular process that underlies the process of fibrosis, a deadly complication of fibrotic diseases like Scleroderma (SSc). This transition coincides with the overproduction of Collagen type I (COL1) and other extracellular matrix proteins. High level expression of the collagen type 1α2 subunit (COL1A2), requires the engagement of a far upstream enhancer, whose activation is strongly dependent on the AP1 factor JunB. We now report that STAT3 also binds the COL1A2 enhancer and is essential for RNA polymerase recruitment, without affecting JunB binding. STAT3 is required for the increased COL1A2 expression observed in myofibroblasts. We also report that TGFβ partially activates STAT3 and show that inhibiting STAT3 potently blocks TGFβ signalling, matrix remodelling and TGFβ-induced myofibroblast differentiation. Activation of STAT3 with IL6 trans-signalling alone however only increased COL1A2 protein expression, leaving COL1A2 mRNA levels unchanged. Our results suggest that activated STAT3 is not the limiting factor for collagen enhancer activation in human lung fibroblasts. Yet, a certain threshold level of STAT3 activity is essential to support activation of the COL1A2 enhancer and TGFβ signalling in fibroblasts. We propose that STAT3 operates at the post-transcriptional as well as the transcriptional level.

PMID: 29142074 [PubMed - as supplied by publisher]




GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes which moderates Aβ production.

GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes which moderates Aβ production.

Mol Biol Cell. 2017 Nov 15;:

Authors: Toh WH, Chia PZC, Hossain MI, Gleeson PA

Abstract
The diversion of the membrane-bound β-secretase BACE1 from the endo-lysosomal pathway to recycling endosomes represents an important transport step in the regulation of amyloid beta (Aβ) production. However, the mechanisms that regulate endosome sorting of BACE1 are poorly understood. Here we assessed the transport of BACE1 from early to recycling endosomes and have identified essential roles for the SNX4-mediated, signal independent pathway and for a novel signal-mediated pathway. The signal-mediated pathway is regulated by the phosphorylation of the acidic cluster-dileucine DISLL cytoplasmic tail motif of BACE1. The phosphomimetic S498D BACE1 mutant was trafficked to recycling endosomes at a faster rate compared with wild-type BACE1 or the non-phosphorylatable S498A mutant. The rapid transit of BACE1 S498D from early endosomes was coupled with reduced levels of amyloid precursor protein processing and Aβ production, compared with the S498A mutant. We show that the adaptor, GGA1, and retromer are essential to mediate rapid trafficking of phosphorylated BACE1 to recycling endosomes. In addition, the BACE1 DISLL motif is phosphorylated, and regulates endosomal trafficking, in primary neurons. Therefore, post-translational phosphorylation of DISLL enhances the exit of BACE1 from early endosomes, a pathway mediated by GGA1 and retromer, which is important in regulating Aβ production.

PMID: 29142073 [PubMed - as supplied by publisher]




Salt Bridges Gate Alpha-Catenin Activation at Intercellular Junctions.

Salt Bridges Gate Alpha-Catenin Activation at Intercellular Junctions.

Mol Biol Cell. 2017 Nov 15;:

Authors: Barrick S, Li J, Kong X, Ray A, Tajkhorshid E, Leckband D

Abstract
Cadherin complexes transduce force fluctuations at junctions to activate signals that reinforce stressed intercellular contacts. α-Catenin is an identified force transducer within cadherin complexes that is autoinhibited under low tension. Increased force triggers a conformational change that exposes a cryptic site for the actin-binding protein vinculin. This study tested predictions that salt bridges within the force-sensing core modulate α-catenin activation. Studies with a fluorescence resonance energy transfer (FRET)-based α-catenin conformation sensor demonstrated that the salt-bridge mutations R551A and D503N each enhance α-catenin activation in live cells, but R551A has a greater impact. Under dynamic force loading at reannealing cell-cell junctions, the R551A mutant bound more vinculin than wild-type α-catenin. In vitro binding measurements quantified the impact of the R551A mutation on the free energy difference between the active and autoinhibited α-catenin conformers. A two-microsecond, constant-force steered molecular dynamics simulation of the core force-sensing region suggested how the salt-bridge mutants alter the α-catenin conformation, and identified a novel load-bearing salt bridge. These results reveal key structural features that determine the force-transduction mechanism and the force sensitivity of this crucial nanomachine.

PMID: 29142072 [PubMed - as supplied by publisher]




Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins.

Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins.

Mol Biol Cell. 2017 Nov 15;:

Authors: Stephens AD, Liu PZ, Banigan EJ, Almassalha LM, Backman V, Adam SA, Goldman RD, Marko JF

Abstract
Nuclear shape and architecture influence gene localization, mechanotransduction, transcription, and cell function. Abnormal nuclear morphology and protrusions termed "blebs" are diagnostic markers for many human afflictions including heart disease, aging, progeria, and cancer. Nuclear blebs are associated with both lamin and chromatin alterations. A number of prior studies suggest that lamins dictate nuclear morphology, but the contributions of altered chromatin compaction remain unclear. We show that chromatin histone modification state dictates nuclear rigidity, and modulating it is sufficient to both induce and suppress nuclear blebs. Treatment of mammalian cells with histone deacetylase inhibitors to increase euchromatin or histone methyltransferase inhibitors to decrease heterochromatin results in a softer nucleus and nuclear blebbing, without perturbing lamins. Oppositely, treatment with histone demethylase inhibitors increases heterochromatin and chromatin nuclear rigidity, which results in reduced nuclear blebbing in lamin B1 null nuclei. Notably, increased heterochromatin also rescues nuclear morphology in a model cell line for the accelerated aging disease Hutchinson-Gilford progeria syndrome caused by mutant lamin A, as well as cells from patients with the disease. Thus, chromatin histone modification state is a major determinant of nuclear blebbing and morphology via its contribution to nuclear rigidity.

PMID: 29142071 [PubMed - as supplied by publisher]




Gfap and Osmr regulation by BRG1 and STAT3 via interchromosomal gene clustering in astrocytes.

Gfap and Osmr regulation by BRG1 and STAT3 via interchromosomal gene clustering in astrocytes.

Mol Biol Cell. 2017 Nov 15;:

Authors: Ito K, Noguchi A, Uosaki Y, Taga T, Arakawa H, Takizawa T

Abstract
Long-range chromatin interactions between gene loci in the cell nucleus are important for many biological processes including transcriptional regulation. Previously, we demonstrated that several genes specifically cluster with the astrocyte-specific gene glial fibrillary acidic protein (Gfap) during astrocyte differentiation; however, the molecular mechanisms for gene clustering remain largely unknown. Here we show that brahma-related gene 1 (BRG1), an ATP-dependent chromatin remodeling factor, and the transcription factor STAT3 are required for Gfap and Osmr clustering and enhanced expression through recruitment to STAT3 recognition sequences and that gene clustering occurs prior to transcriptional upregulation. BRG1 knockdown and JAK-STAT signaling inhibition impaired clustering, leading to transcriptional downregulation of both genes. BRG1 and STAT3 were recruited to the same Gfap fragment; JAK-STAT signaling inhibition impaired BRG1 recruitment. Our results suggest that BRG1 and STAT3 coordinately regulate gene clustering and upregulate Gfap and Osmr transcription.

PMID: 29142070 [PubMed - as supplied by publisher]