cellular mechanism
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2022 ◽  
Vol 13 (2) ◽  
pp. 373-384
Author(s):  
Paleerath Peerapen ◽  
Kanyarat Sueksakit ◽  
Wanida Boonmark ◽  
Sunisa Yoodee ◽  
Visith Thongboonkerd

2021 ◽  
Vol 12 ◽  
Author(s):  
Shinrye Lee ◽  
Myungjin Jo ◽  
Hye Eun Lee ◽  
Yu-Mi Jeon ◽  
Seyeon Kim ◽  
...  

The autophagy-lysosomal pathway is an essential cellular mechanism that degrades aggregated proteins and damaged cellular components to maintain cellular homeostasis. Here, we identified HEXA-018, a novel compound containing a catechol derivative structure, as a novel inducer of autophagy. HEXA-018 increased the LC3-I/II ratio, which indicates activation of autophagy. Consistent with this result, HEXA-018 effectively increased the numbers of autophagosomes and autolysosomes in neuronal cells. We also found that the activation of autophagy by HEXA-018 is mediated by the AMPK-ULK1 pathway in an mTOR-independent manner. We further showed that ubiquitin proteasome system impairment- or oxidative stress-induced neurotoxicity was significantly reduced by HEXA-018 treatment. Moreover, oxidative stress-induced mitochondrial dysfunction was strongly ameliorated by HEXA-018 treatment. In addition, we investigated the efficacy of HEXA-018 in models of TDP-43 proteinopathy. HEXA-018 treatment mitigated TDP-43 toxicity in cultured neuronal cell lines and Drosophila. Our data indicate that HEXA-018 could be a new drug candidate for TDP-43-associated neurodegenerative diseases.


2021 ◽  
Author(s):  
Annie Lauzier ◽  
Marie-France Bossanyi ◽  
Raphaëlle Larcher ◽  
Sonya Nassari ◽  
Rupali Ugrankar ◽  
...  

Macroautophagy, the degradation and recycling of cytosolic components in the lysosome, is an important cellular mechanism. It is a membrane-mediated process that is linked to vesicular trafficking events. The sorting nexin (SNX) protein family controls the sorting of a large array of cargoes, and various SNXs impact autophagy. To improve our understanding of their functions in vivo, we screened all Drosophila SNXs using inducible RNA interference in the fat body. Significantly, depletion of snazarus (snz) led to decreased autophagic flux. Interestingly, we observed altered distribution of Vamp7-positive vesicles with snz depletion, and snz's roles were conserved in human cells. SNX25, the closest human ortholog to snz, regulates both VAMP8 endocytosis and lipid metabolism. Through knockout-rescue experiments, we demonstrate that these activities are dependent on specific SNX25 domains and that the autophagic defects upon SNX25 loss can be rescued by ethanolamine addition. We also demonstrate the presence of differentially spliced forms of SNX14 and SNX25 in cancer cells. This work identifies a conserved role for snz/SNX25 as regulators of autophagic flux and reveals differential isoform expression between paralogs.


2021 ◽  
Author(s):  
Tomas Marvan ◽  
Michal Polák ◽  
Talis Bachmann ◽  
William A. Phillips

We present a theoretical view of the cellular foundations fornetwork-level processes involved in producing our conscious experience.Inputs to apical synapses in layer 1 of a large subset of neocortical cellsare summed at an integration zone near the top of their apical trunk. Theseinputs come from diverse sources, and provide a context within which thetransmission of information abstracted from sensory input to their basal andperisomatic synapses can be amplified when relevant. We argue that apicalamplification (AA) enables conscious perceptual experience and makes it moreflexible, and thus more adaptive, by being sensitive to context. AA providesa possible mechanism for recurrent processing theory that avoids strongloops. It makes the broadcasting hypothesized by global neuronal workspacetheories feasible while preserving the distinct contributions of theindividual cells receiving the broadcast. It also provides mechanisms thatcontribute to the holistic aspects of integrated information theory. As AAis highly dependent on cholinergic, aminergic, and other neuromodulators, itrelates the specific contents of conscious experience to global mental statesand to fluctuations in arousal when awake. We conclude that apical dendritesprovide a cellular mechanism for the context-sensitive selectiveamplification that is a cardinal prerequisite of conscious perception.


2021 ◽  
Author(s):  
Yu Xiao ◽  
Wan Jin ◽  
Kaiyu Qian ◽  
Kai Wu ◽  
Gang Wang ◽  
...  

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.


2021 ◽  
Vol 2021 (2) ◽  
Author(s):  
Tomáš Marvan ◽  
Michal Polák ◽  
Talis Bachmann ◽  
William A Phillips

Abstract We present a theoretical view of the cellular foundations for network-level processes involved in producing our conscious experience. Inputs to apical synapses in layer 1 of a large subset of neocortical cells are summed at an integration zone near the top of their apical trunk. These inputs come from diverse sources and provide a context within which the transmission of information abstracted from sensory input to their basal and perisomatic synapses can be amplified when relevant. We argue that apical amplification enables conscious perceptual experience and makes it more flexible, and thus more adaptive, by being sensitive to context. Apical amplification provides a possible mechanism for recurrent processing theory that avoids strong loops. It makes the broadcasting hypothesized by global neuronal workspace theories feasible while preserving the distinct contributions of the individual cells receiving the broadcast. It also provides mechanisms that contribute to the holistic aspects of integrated information theory. As apical amplification is highly dependent on cholinergic, aminergic, and other neuromodulators, it relates the specific contents of conscious experience to global mental states and to fluctuations in arousal when awake. We conclude that apical dendrites provide a cellular mechanism for the context-sensitive selective amplification that is a cardinal prerequisite of conscious perception.


Author(s):  
Laura Gauthier ◽  
Peggy Charbonnier ◽  
Mireille Chevallet ◽  
Pascale Delangle ◽  
Isabelle Texier ◽  
...  

2021 ◽  
Author(s):  
Lanxin Li ◽  
Inge Verstraeten ◽  
Mark Roosjen ◽  
Koji Takahashi ◽  
Lesia Rodriguez ◽  
...  

Abstract Growth regulation tailors plant development to its environment. A showcase is response to gravity, where shoots bend up and roots down1. This paradox is based on opposite effects of the phytohormone auxin, which promotes cell expansion in shoots, while inhibiting it in roots via a yet unknown cellular mechanism2. Here, by combining microfluidics, live imaging, genetic engineering and phospho-proteomics in Arabidopsis thaliana, we advance our understanding how auxin inhibits root growth. We show that auxin activates two distinct, antagonistically acting signalling pathways that converge on the rapid regulation of the apoplastic pH, a causative growth determinant. Cell surface-based TRANSMEMBRANE KINASE1 (TMK1) interacts with and mediates phosphorylation and activation of plasma membrane H+-ATPases for apoplast acidification, while intracellular canonical auxin signalling promotes net cellular H+-influx, causing apoplast alkalinisation. The simultaneous activation of these two counteracting mechanisms poises the root for a rapid, fine-tuned growth modulation while navigating complex soil environment.


Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1317
Author(s):  
Sigalit Sukenik ◽  
Ilana Braunstein ◽  
Ariel Stanhill

Maintaining 26S proteasome activity under diverse physiological conditions is a fundamental requirement in order to maintain cellular proteostasis. Several quantitative and qualitative mechanisms have evolved to ensure that ubiquitin–proteasome system (UPS) substrates do not accumulate and lead to promiscuous protein–protein interactions that, in turn, lead to cellular malfunction. In this report, we demonstrate that Arsenite Inducible Regulatory Particle-Associate Protein (AIRAP), previously reported as a proteasomal adaptor required for maintaining proteasomal flux during arsenite exposure, can directly bind arsenite molecules. We further show that arsenite inhibits Psmd14/Rpn11 metalloprotease deubiquitination activity by substituting zinc binding to the MPN/JAMM domain. The proteasomal adaptor AIRAP is able to directly relieve PSMD14/Rpn11 inhibition. A possible metal relay between arsenylated PSMD14/Rpn11 and AIRAP may serve as a cellular mechanism that senses proteasomal inhibition to restore Psmd14/Rpn11 activity.


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