bims-lypmec 2022-12-18 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2022–12–18
nine papers selected by
Satoru Kobayashi, New York Institute of Technology

Lysosome signaling in cell survival and programmed cell death for cellular homeostasis.
Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB.
ATG9A prevents TNF cytotoxicity by an unconventional lysosomal targeting pathway.
Molecular insights into endolysosomal microcompartment formation and maintenance.
CHIP: A Co-chaperone for Degradation by the Proteasome and Lysosome.
Protocol and Software for Automated Detection of Lysosome Active "Runs" and "Flights" with Wavelet Transform Approach.
Editorial: Cell compartments and intracellular trafficking of lipids and proteins: Impact on biomedicine.
p38 MAPK-dependent phosphorylation of TFEB promotes monocyte-to-macrophage differentiation.
Diversity of mitophagy pathways at a glance.

J Cell Physiol. 2022 Dec 11.

Lysosome signaling in cell survival and programmed cell death for cellular homeostasis.

Srimanta Patra, Shankargouda Patil, Daniel J Klionsky, Sujit K Bhutia.

  Recent developments in lysosome biology have transformed our view of lysosomes from static garbage disposals that can also act as suicide bags to decidedly dynamic multirole adaptive operators of cellular homeostasis. Lysosome-governed signaling pathways, proteins, and transcription factors equilibrate the rate of catabolism and anabolism (autophagy to lysosomal biogenesis and metabolite pool maintenance) by sensing cellular metabolic status. Lysosomes also interact with other organelles by establishing contact sites through which they exchange cellular contents. Lysosomal function is critically assessed by lysosomal positioning and motility for cellular adaptation. In this setting, mechanistic target of rapamycin kinase (MTOR) is the chief architect of lysosomal signaling to control cellular homeostasis. Notably, lysosomes can orchestrate explicit cell death mechanisms, such as autophagic cell death and lysosomal membrane permeabilization-associated regulated necrotic cell death, to maintain cellular homeostasis. These lines of evidence emphasize that the lysosomes serve as a central signaling hub for cellular homeostasis.

Keywords:  autophagy; lysosomal biogenesis; lysosomal membrane permeabilization; lysosome; mechanistic target of rapamycin kinase

DOI:  https://doi.org/10.1002/jcp.30928
Cell Death Dis. 2022 Dec 16. 13(12): 1047

Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB.

Belén Fernández, Pablo Olmedo, Fernando Gil, Elena Fdez, Yahaira Naaldijk, Pilar Rivero-Ríos, Franz Bracher, Christian Grimm, Grant C Churchill, Sabine Hilfiker.

Increased brain iron content has been consistently reported in sporadic Parkinson's disease (PD) patients, and an increase in cytosolic free iron is known to cause oxidative stress and cell death. However, whether iron also accumulates in susceptible brain areas in humans or in mouse models of familial PD remains unknown. In addition, whilst the lysosome functions as a critical intracellular iron storage organelle, little is known about the mechanisms underlying lysosomal iron release and how this process is influenced by lysosome biogenesis and/or lysosomal exocytosis. Here, we report an increase in brain iron content also in PD patients due to the common G2019S-LRRK2 mutation as compared to healthy age-matched controls, whilst differences in iron content are not observed in G2019S-LRRK2 knockin as compared to control mice. Chemically triggering iron overload in cultured cells causes cytotoxicity via the endolysosomal release of iron which is mediated by TRPML1. TFEB expression reverts the iron overload-associated cytotoxicity by causing lysosomal exocytosis, which is dependent on a TRPML1-mediated increase in cytosolic calcium levels. Therefore, approaches aimed at increasing TFEB levels, or pharmacological TRPML1 activation in conjunction with iron chelation may prove beneficial against cell death associated with iron overload conditions such as those associated with PD.

DOI: https://doi.org/10.1038/s41419-022-05504-2
Science. 2022 Dec 16. 378(6625): 1201-1207

ATG9A prevents TNF cytotoxicity by an unconventional lysosomal targeting pathway.

Jon Huyghe, Dario Priem, Lisette Van Hove, Barbara Gilbert, Jürgen Fritsch, Yasuo Uchiyama, Esther Hoste, Geert van Loo, Mathieu J M Bertrand.

Cell death induced by tumor necrosis factor (TNF) can be beneficial during infection by helping to mount proper immune responses. However, TNF-induced death can also drive a variety of inflammatory pathologies. Protectives brakes, or cell-death checkpoints, normally repress TNF cytotoxicity to protect the organism from its potential detrimental consequences. Thus, although TNF can kill, this only occurs when one of the checkpoints is inactivated. Here, we describe a checkpoint that prevents apoptosis through the detoxification of the cytotoxic complex IIa that forms upon TNF sensing. We found that autophagy-related 9A (ATG9A) and 200kD FAK family kinase-interacting protein (FIP200) promote the degradation of this complex through a light chain 3 (LC3)-independent lysosomal targeting pathway. This detoxification mechanism was found to counteract TNF receptor 1 (TNFR1)-mediated embryonic lethality and inflammatory skin disease in mouse models.

DOI: https://doi.org/10.1126/science.add6967
Biol Chem. 2022 Dec 13.

Molecular insights into endolysosomal microcompartment formation and maintenance.

Daniel Kümmel, Eric Herrmann, Lars Langemeyer, Christian Ungermann.

  The endolysosomal system of eukaryotic cells has a key role in the homeostasis of the plasma membrane, in signaling and nutrient uptake, and is abused by viruses and pathogens for entry. Endocytosis of plasma membrane proteins results in vesicles, which fuse with the early endosome. If destined for lysosomal degradation, these proteins are packaged into intraluminal vesicles, converting an early endosome to a late endosome, which finally fuses with the lysosome. Each of these organelles has a unique membrane surface composition, which can form segmented membrane microcompartments by membrane contact sites or fission proteins. Furthermore, these organelles are in continuous exchange due to fission and fusion events. The underlying machinery, which maintains organelle identity along the pathway, is regulated by signaling processes. Here, we will focus on the Rab5 and Rab7 GTPases of early and late endosomes. As molecular switches, Rabs depend on activating guanine nucleotide exchange factors (GEFs). Over the last years, we characterized the Rab7 GEF, the Mon1-Ccz1 (MC1) complex, and key Rab7 effectors, the HOPS complex and retromer. Structural and functional analyses of these complexes lead to a molecular understanding of their function in the context of organelle biogenesis.

Keywords:  GEF; HOPS; endosome; lysosome; membrane fusion; tethering

DOI:  https://doi.org/10.1515/hsz-2022-0294
Subcell Biochem. 2023 ;101 351-387

CHIP: A Co-chaperone for Degradation by the Proteasome and Lysosome.

Abantika Chakraborty, Adrienne L Edkins.

  Protein homeostasis relies on a balance between protein folding and protein degradation. Molecular chaperones like Hsp70 and Hsp90 fulfill well-defined roles in protein folding and conformational stability via ATP-dependent reaction cycles. These folding cycles are controlled by associations with a cohort of non-client protein co-chaperones, such as Hop, p23, and Aha1. Pro-folding co-chaperones facilitate the transit of the client protein through the chaperone-mediated folding process. However, chaperones are also involved in proteasomal and lysosomal degradation of client proteins. Like folding complexes, the ability of chaperones to mediate protein degradation is regulated by co-chaperones, such as the C-terminal Hsp70-binding protein (CHIP/STUB1). CHIP binds to Hsp70 and Hsp90 chaperones through its tetratricopeptide repeat (TPR) domain and functions as an E3 ubiquitin ligase using a modified RING finger domain (U-box). This unique combination of domains effectively allows CHIP to network chaperone complexes to the ubiquitin-proteasome and autophagosome-lysosome systems. This chapter reviews the current understanding of CHIP as a co-chaperone that switches Hsp70/Hsp90 chaperone complexes from protein folding to protein degradation.

Keywords:  Autophagy; CHIP; Co-chaperones; Lysosome; Proteasome; STUB1; Ubiquitin

DOI:  https://doi.org/10.1007/978-3-031-14740-1_12
Methods Mol Biol. 2023 ;2593 171-195

Protocol and Software for Automated Detection of Lysosome Active "Runs" and "Flights" with Wavelet Transform Approach.

Kristiana Kandere-Grzybowska, Konstantin Polev, Diana V Kolygina, Bartosz A Grzybowski.

  Lysosomes are highly dynamic degradation/recycling organelles that harbor sophisticated molecular sensors and signal transduction machinery through which they control cell adaptation to environmental cues and nutrients. The movements of these signaling hubs comprise persistent, directional runs-active, ATP-dependent transport along the microtubule tracks-interspersed by short, passive movements and pauses imposed by cytoplasmic constraints. The trajectories of individual lysosomes are usually obtained by time-lapse imaging of the acidic organelles labeled with LysoTracker dyes or fluorescently-tagged lysosomal-associated membrane proteins LAMP1 and LAMP2. Subsequent particle tracking generates large data sets comprising thousands of lysosome trajectories and hundreds of thousands of data points. Analyzing such data sets requires unbiased, automated methods to handle large data sets while capturing the temporal heterogeneity of lysosome trajectory data. This chapter describes integrated and largely automated workflow from live cell imaging to lysosome trajectories to computing the parameters of lysosome dynamics. We describe an open-source code for implementing the continuous wavelet transform (CWT) to distinguish trajectory segments corresponding to active transport (i.e., "runs" and "flights") versus passive lysosome movements. Complementary cumulative distribution functions (CDFs) of the "runs/flights" are generated, and Akaike weight comparisons with several competing models (lognormal, power law, truncated power law, stretched exponential, exponential) are performed automatically. Such high-throughput analyses yield useful aggregate/ensemble metrics for lysosome active transport.

Keywords:  ADP-ribosylation factor-like protein 8B; Active transport; Cumulative distribution function; Lognormal distribution; LysoTracker dyes; Movement patterns; Multiscale wavelets; Run length

DOI:  https://doi.org/10.1007/978-1-0716-2811-9_11
Front Cell Dev Biol. 2022 ;10 1087214

Editorial: Cell compartments and intracellular trafficking of lipids and proteins: Impact on biomedicine.

Silvana Zanlungo, Carlos Enrich, Volker Gerke, Emily R Eden, María Isabel Colombo.



Keywords:  Endosomes; cholesterol; disease models; lipid droplets; lysosomal storage diseases; lysosome-related organelles; lysosomes; membrane contact sites

DOI:  https://doi.org/10.3389/fcell.2022.1087214
EMBO Rep. 2022 Dec 12. e55472

p38 MAPK-dependent phosphorylation of TFEB promotes monocyte-to-macrophage differentiation.

José A Martina, Eutteum Jeong, Rosa Puertollano.

  The transcription factor EB (TFEB) regulates energy homeostasis and cellular response to a wide variety of stress conditions, including nutrient deprivation, oxidative stress, organelle damage, and pathogens. Here we identify S401 as a novel phosphorylation site within the TFEB proline-rich domain. Phosphorylation of S401 increases significantly in response to oxidative stress, UVC light, growth factors, and LPS, whereas this increase is prevented by p38 MAPK inhibition or depletion, revealing a new role for p38 MAPK in TFEB regulation. Mutation of S401 in THP1 cells demonstrates that the p38 MAPK/TFEB pathway plays a particularly relevant role during monocyte differentiation into macrophages. TFEB-S401A monocytes fail to upregulate the expression of multiple immune genes in response to PMA-induced differentiation, including critical cytokines, chemokines, and growth factors. Polarization of M0 macrophages into M1 inflammatory macrophages is also aberrant in TFEB-S401A cells. These results indicate that TFEB-S401 phosphorylation links differentiation signals to the transcriptional control of monocyte differentiation.

Keywords:  TFEB; autophagy; lysosomes; monocytes; p38 MAPK

DOI:  https://doi.org/10.15252/embr.202255472
J Cell Sci. 2022 Dec 01. pii: jcs259748. [Epub ahead of print]135(23):

Diversity of mitophagy pathways at a glance.

Ian G Ganley, Anne Simonsen.

  Mitochondria are crucial organelles that play a central role in various cell signaling and metabolic pathways. A healthy mitochondrial population is maintained through a series of quality control pathways and requires a fine-tuned balance between mitochondrial biogenesis and degradation. Defective targeting of dysfunctional mitochondria to lysosomes through mitophagy has been linked to several diseases, but the underlying mechanisms and the relative importance of distinct mitophagy pathways in vivo are largely unknown. In this Cell Science at a Glance and the accompanying poster, we describe our current understanding of how parts of, or whole, mitochondria are recognized by the autophagic machinery and targeted to lysosomes for degradation. We also discuss how this might be regulated under different physiological conditions to maintain mitochondrial and cellular health.

Keywords:  BNIP3; HIF1; Mitochondria; Mitophagy; NIX; PINK1; Parkin; SLR; Selective autophagy

DOI:  https://doi.org/10.1242/jcs.259748