ABIN1 is a negative regulator of effector functions in cytotoxic T cells DOI Creative Commons
Sarka Janusova, Darina Paprčková, Juraj Michálik

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 30, 2023

Abstract T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by T-cell antigen receptors (TCR) co-stimulatory or inhibitory receptors. The molecular regulation of these complex networks is still incompletely understood. We identified an adaptor protein, ABIN1 as component complexes GITR OX40 co-stimulation lacking hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, superior ability induce experimental autoimmune diabetes mice. observed that negatively regulates NF-κB p38 pathways. latter was at least partially responsible for upregulation key effector proteins, IFNG GZMB ABIN1-deficient after TCR stimulation. Our findings reveal role its potential target therapeutic fine-tuning responses.

Language: Английский

Mitophagy for cardioprotection DOI Creative Commons
Allen Sam Titus, Eun‐Ah Sung,

Daniela Zablocki

et al.

Basic Research in Cardiology, Journal Year: 2023, Volume and Issue: 118(1)

Published: Oct. 5, 2023

Abstract Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control including fusion and fission, degradation, biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are central organelle for maintaining cardiac function. Since adult cardiomyocytes humans rarely divide, number dysfunctional cannot easily be diluted through cell division. Thus, efficient degradation crucial to cellular Mitophagy, a specific form autophagy, major mechanism which damaged or unnecessary targeted eliminated. Mitophagy active at baseline response stress, plays an essential role cardiomyocytes. mediated multiple mechanisms heart, each these can partially compensate loss another mechanism. However, insufficient levels mitophagy eventually lead dysfunction development heart failure. In this review, we discuss molecular pathophysiology, with focus on recent findings field.

Language: Английский

Citations

49
Nix interacts with WIPI2 to induce mitophagy DOI Creative Commons
Eric Bunker, François Le Guerroué, Chunxin Wang

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(22)

Published: Aug. 25, 2023

Nix is a membrane-anchored outer mitochondrial protein that induces mitophagy. While has an LC3-interacting (LIR) motif binds to ATG8 proteins, it also contains minimal essential region (MER) mitophagy through unknown mechanism. We used chemically induced dimerization (CID) probe the mechanism of Nix-mediated and found both LIR MER are required for robust find interacts with autophagy effector WIPI2 recruits mitochondria. The converts homogeneous distribution on surface mitochondria into puncta, even in absence ATG8s. Together, this work reveals unanticipated mechanisms Nix-induced elusive role MER, while describing interesting example induction acts downstream canonical initiation complexes.

Language: Английский

Citations

24
Mechanism and role of mitophagy in the development of severe infection DOI Creative Commons

Lixiu Ma,

Tianyu Han,

Y M Zhan

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 19, 2024

Abstract Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction mitophagy abnormalities. Restoring protects against excessive inflammation multiple organ failure sepsis. Here, we review normal process, its interaction with invading microorganisms immune system, summarize mechanism of during infection. We highlight critical role preventing

Language: Английский

Citations

13
Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD DOI Creative Commons
Elias Adriaenssens, Thanh Ngoc Nguyen, Justyna Sawa‐Makarska

et al.

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(11), P. 1717 - 1731

Published: June 25, 2024

Abstract Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding 1) adaptors NAP1 (NAK-associated protein SINTBAD (similar to adaptor) restrict initiation of OPTN (optineurin)-driven competing with TBK1. Conversely, they promote nuclear dot 52 (NDP52)-driven recruiting NDP52 stabilizing its interaction FIP200. Notably, emerges as primary recruiter during initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define cargo receptor rheostats, elevating threshold promoting pathway set motion supporting NDP52. These findings shed light on cellular strategy hyperactivity still efficient progression.

Language: Английский

Citations

11
Did mitophagy follow the origin of mitochondria? DOI
Mauro Degli Esposti

Autophagy, Journal Year: 2024, Volume and Issue: 20(5), P. 985 - 993

Published: Feb. 15, 2024

Mitophagy is the process of selective autophagy that removes superfluous and dysfunctional mitochondria. was first characterized in mammalian cells now recognized to follow several pathways including basal forms specific organs. are regulated by multiple, often interconnected factors. The present review aims streamline this complexity evaluate common elements may define evolutionary origin mitophagy. Key issues surrounding mitophagy signaling at mitochondrial surface fundamentally derive from membrane dynamics. Elements such dynamics likely originated during endosymbiosis alphaproteobacterial ancestor our mitochondria but underwent an leap forward metazoa determined currently known variations signaling.

Language: Английский

Citations

10
A TNIP1-driven systemic autoimmune disorder with elevated IgG4 DOI Creative Commons
Arti Medhavy, Vicki Athanasopoulos,

Katharine Bassett

et al.

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(9), P. 1678 - 1691

Published: July 26, 2024

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1

Language: Английский

Citations

5
A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy DOI Creative Commons
Angelina S. Gross, Ruben Ghillebert,

M. Schuetter

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(3), P. 366 - 377

Published: Feb. 5, 2024

Abstract Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK (AKC) to induce non-selective and selective forms of in response changes. Here we show that, upon phosphate starvation, metabolite sensor Pho81 interacts with adaptor subunit Atg11 at AKC via an Atg11/FIP200 interaction motif modulate pexophagy by virtue its phospho-metabolite sensing SPX domain. Notably, core components Atg13 Atg17 are dispensable for starvation-induced revealing significant compositional functional plasticity AKC. Our data indicate instead functioning as a receptor, compensates partially inactive promoting phosphorylation Atg1 critical during starvation. work shows subunits bind not only receptors but also modulator that convey directly regulation.

Language: Английский

Citations

4
The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization DOI Creative Commons
Devanarayanan Siva Sankar, Stéphanie Pébernard,

Christine Vionnet

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(9), P. 114689 - 114689

Published: Aug. 27, 2024

Autophagy initiation is regulated by the ULK1 kinase complex. To gain insights into functions of holo-complex, we generated a deep interactome combining affinity purification- and proximity labeling-mass spectrometry all four complex members: ULK1, ATG13, ATG101, RB1CC1/FIP200. Under starvation conditions, interacts with several protein lipid kinases phosphatases, implying formation signalosome. Interestingly, selective autophagy receptors also interact indicating activation pathways nutrient starvation. One effector HSC/HSP70 co-chaperone BAG2, which regulates subcellular localization VPS34 member AMBRA1. Depending on nutritional status, BAG2 has opposing roles. In growth unphosphorylated form sequesters AMBRA1, attenuating induction. phosphorylates Ser31, supports recruitment AMBRA1 to ER membrane, positively affecting autophagy.

Language: Английский

Citations

4
Trem2 deficiency attenuates microglial phagocytosis and autophagic‐lysosomal activation in white matter hypoperfusion DOI

Xiao‐Wei Pang,

Yun‐Hui Chu,

Luo‐Qi Zhou

et al.

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 167(4), P. 489 - 504

Published: Oct. 12, 2023

Abstract Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is exclusively microglia in the central nervous system (CNS), plays an essential role microglial various CNS disorders. However, specific Trem2 chronic has not been elucidated. In this study, we investigated mouse model induced by bilateral carotid artery stenosis (BCAS). Our results showed that white matter demyelination, phagocytosis, activation autophagic‐lysosomal pathway, accompanied increase expression. After knockout, observed attenuation lesions response. deficiency also suppressed phagocytosis relieved leading polarization towards anti‐inflammatory homeostatic phenotypes. Furthermore, knockout inhibited lipid droplet accumulation vitro. Collectively, these findings suggest ameliorated hypoperfusion‐induced injury, could be promising target for treatment hypoperfusion. image

Language: Английский

Citations

10
The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux DOI

Brian J. North,

Amelia E Ohnstad, Michael J. Ragusa

et al.

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(4)

Published: Jan. 8, 2025

During autophagy, toxic cargo is encapsulated by autophagosomes and trafficked to lysosomes for degradation. NBR1, an autophagy receptor targeting ubiquitinated aggregates, serves as a model studying the multivalent, heterotypic interactions of cargo-bound receptors. Here, we find that three critical NBR1 partners—ATG8-family proteins, FIP200, TAX1BP1—each bind distinct, overlapping determinants within short linear interaction motif (SLiM). To explore whether SLiMs extend beyond analyzed >100 LC3-interacting regions (LIRs), revealing FIP200 and/or TAX1BP1 binding LIRs common phenomenon suggesting protein hotspots. Phosphomimetic peptides demonstrate phosphorylation generally enhances ATG8-family but not TAX1BP1, indicating differential regulation. In vivo, LIR-mediated with promote optimal flux leveraging additional functionalities from TAX1BP1. These findings reveal one-to-many modality in LIR illustrating cooperative mechanisms receptors regulatory potential multifunctional SLiMs.

Language: Английский

Citations

0