Phosphorylation of KRT8 (keratin 8) by excessive mechanical load-activated PKN (protein kinase N) impairs autophagosome initiation and contributes to disc degeneration

Autophagy, Journal Year: 2023, Volume and Issue: 19(9), P. 2485 - 2503

Published: March 10, 2023

Excessive mechanical load (overloading) is a well-documented pathogenetic factor for many mechano stress-induced pathologies, i.e. intervertebral disc degeneration (IDD). Under overloading, the balance between anabolism and catabolism within nucleus pulposus (NP) cells are badly thrown off, NP undergo apoptosis. However, little known about how overloading transduced to contributes degeneration. The current study shows that conditional knockout of Krt8 (keratin 8) aggravates load-induced IDD in vivo, overexpression endows greater resistance overloading-induced apoptosis vitro. Discovery-driven experiments phosphorylation KRT8 on Ser43 by activated RHOA-PKN (protein kinase N) impedes trafficking Golgi resident small GTPase RAB33B, suppresses autophagosome initiation IDD. Overexpression knockdown Pkn1 Pkn2, at an early stage IDD, ameliorates degeneration; yet only when treated late therapeutic effect. This validates protective role during demonstrates targeting activation PKNs could be novel effective approach pathologies with wider window opportunity.

Language: Английский

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The Force is Strong with This Epigenome: Chromatin Structure and Mechanobiology

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(11), P. 168019 - 168019

Published: June 1, 2023

All life forms sense and respond to mechanical stimuli. Throughout evolution, organisms develop diverse mechanosensing mechanotransduction pathways, leading fast sustained mechanoresponses. Memory plasticity characteristics of mechanoresponses are thought be stored in the form epigenetic modifications, including chromatin structure alterations. These context share conserved principles across species, such as lateral inhibition during organogenesis development. However, it remains unclear how mechanisms alter for specific cellular functions, if altered can mechanically affect environment. In this review, we discuss is by environmental forces via an outside-in pathway emerging concept alterations nuclear, cellular, extracellular environments. This bidirectional feedback between cell environment potentially have important physiological implications, centromeric regulation mechanobiology mitosis, or tumor-stroma interactions. Finally, highlight current challenges open questions field provide perspectives future research.

Language: Английский

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DNA‐based Precision Tools to Probe and Program Mechanobiology and Organ Engineering

Small, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

DNA nanotechnology represents an innovative discipline that combines with biotechnology. It exploits the distinctive characteristics of deoxyribonucleic acid (DNA) to create nanoscale structures and devices remarkable accuracy functionality. Researchers may complex nanostructures precision specialized functions using DNA's innate stability, adaptability, capacity self-assemble through complementary base-pairing interactions. Integrating multiple disciplines, known as nanobiotechnology, allows production sophisticated nanodevices a broad range applications. These include precise drug delivery systems, extremely sensitive biosensors, construction intricate tissue scaffolds for regenerative medicine. Moreover, combining mechanobiology provides new understanding how small-scale mechanical stresses molecular interactions affect cellular activity development. has potential revolutionize diagnostics, engineering, organ regeneration. This could lead enormous improvements in biomedicine. review emphasizes most recent developments nanotechnology, explicitly highlighting its significant influence on growing involvement engineering. extensive overview present trends, obstacles, future prospects this fast-progressing area.

Language: Английский

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Feeling the force from within – new tools and insights into nuclear mechanotransduction

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(5)

Published: March 1, 2025

The ability of cells to sense and respond mechanical signals is essential for many biological processes that form the basis cell identity, tissue development maintenance. This process, known as mechanotransduction, involves crucial feedback between force biochemical signals, including epigenomic modifications establish transcriptional programs. These programs, in turn, reinforce properties its withstand perturbation. nucleus has long been hypothesized play a key role mechanotransduction due direct exposure forces transmitted through cytoskeleton, receiving cytoplasmic central function gene regulation. However, parsing out specific contributions from those surface cytoplasm remains substantial challenge. In this Review, we examine latest evidence on how regulates both via nuclear envelope (NE) epigenetic machinery elements within interior. We also explore establishing memory, characterized by mechanical, transcriptomic state persists after stimuli cease. Finally, discuss current challenges field present technological advances are poised overcome them.

Language: Английский

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Mechanically induced alterations in chromatin architecture guide the balance between cell plasticity and mechanical memory

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: April 18, 2023

Phenotypic plasticity, or adaptability, of a cell determines its ability to survive and function within changing cellular environments. Changes in the mechanical environment, ranging from stiffness extracellular matrix (ECM) physical stress such as tension, compression, shear, are critical environmental cues that influence phenotypic plasticity stability. Furthermore, an exposure prior signal has been demonstrated play fundamental role modulating changes persist even after stimulus is removed, creating stable memories. In this mini review, our objective highlight how environment alters both memories through chromatin architecture, mainly focusing on examples cardiac tissue. We first explore modulated response then connect architecture reflect short-term long-term Finally, we discuss elucidating mechanisms behind mechanically induced lead adaptations retention could uncover treatment methods prevent mal-adaptive permanent disease states.

Language: Английский

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Atomic force microscopy-mediated mechanobiological profiling of complex human tissues

Biomaterials, Journal Year: 2023, Volume and Issue: 303, P. 122389 - 122389

Published: Nov. 11, 2023

Tissue mechanobiology is an emerging field with the overarching goal of understanding interplay between biophysical and biochemical responses affecting development, physiology, disease. Changes in mechanical properties including stiffness viscosity have been shown to describe how cells tissues respond cues modify critical biological functions. To quantitatively characterize at physiologically relevant conditions, atomic force microscopy (AFM) has emerged as a highly versatile biomechanical technology. In this review, we fundamental principles AFM, typical AFM modalities used for tissue mechanics, commonly elastic viscoelastic contact mechanics models complex human tissues. Furthermore, discuss application AFM-based within track their developmental, physiological/functional, diseased states, oral, hearing, cancer-related Finally, current outlook challenges further advance mechanobiology. Altogether, provides mechanistic processes governing unique functions

Language: Английский

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The Role of Mechanotransduction in Contact Inhibition of Locomotion and Proliferation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2135 - 2135

Published: Feb. 10, 2024

Contact inhibition (CI) represents a crucial tumor-suppressive mechanism responsible for controlling the unbridled growth of cells, thus preventing formation cancerous tissues. CI can be further categorized into two distinct yet interrelated components: locomotion (CIL) and proliferation (CIP). These components have historically been viewed as separate processes, but emerging research suggests that they may regulated by both shared pathways. Specifically, recent studies indicated CIP CIL utilize mechanotransduction pathways, process involves cells sensing responding to mechanical forces. This review article describes role in CI, shedding light on how forces regulate CIP. Emphasis is placed filamin A (FLNA)-mediated mechanotransduction, elucidating FLNA senses translates them biochemical signals cell proliferation. In addition FLNA, trans-acting factors (TAFs), which are proteins or regulatory RNAs capable directly indirectly binding specific DNA sequences distant genes gene expression, emerge sensitive players signaling pathways CI. presents methods identifying these TAF profiling associated changes chromatin structure, offering valuable insights other biological functions mediated mechanotransduction. Finally, it addresses unanswered questions fields delineates their possible future directions.

Language: Английский

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Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 18, 2024

Abstract Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool stem cells that express LGR5. Whether these distinct populations display different mechanical properties, how properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find compared LGR5- cells, LGR5+ stiffer, adhere better the extracellular matrix (ECM), move slower both as single clusters, higher nuclear YAP, show survival rate in response confinement, form larger transendothelial gaps. These differences largely explained by downregulation membrane cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) cells. By analyzing RNA-sequencing (scRNA-seq) expression patterns from cohort, this robust signature colorectal tumors. Our results mechanically dynamic phenotype suitable for dissemination primary tumor whereas stable resilient extravasation metastatic growth.

Language: Английский

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RAD-TGTs: high-throughput measurement of cellular mechanotype via rupture and delivery of DNA tension probes

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 28, 2023

Mechanical forces drive critical cellular processes that are reflected in mechanical phenotypes, or mechanotypes, of cells and their microenvironment. We present here "Rupture And Deliver" Tension Gauge Tethers (RAD-TGTs) which flow cytometry is used to record the history thousands exerting on surroundings via propensity rupture immobilized DNA duplex tension probes. demonstrate RAD-TGTs recapitulate prior probe studies while also yielding a gain fluorescence force-generating cell detectable by cytometry. Furthermore, altered following disruption cytoskeleton using drugs CRISPR-knockout mechanosensing proteins. Importantly, can differentiate distinct mechanotypes among mixed populations cells. establish oligo delivery be measured sequencing. provide facile powerful assay enable high-throughput mechanotype profiling, could find various applications, for example, combination with CRISPR screens -omics analysis.

Language: Английский

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Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 250, P. 108528 - 108528

Published: Sept. 13, 2023

Language: Английский

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