ATG2 and VPS13 proteins: Molecular highways transporting lipids to drive membrane expansion and organelle communication

Recent studies indicated potential importance of membrane contact sites (MCS) between the endoplasmic reticulum (ER) and other cellular organelles. These MCS have unique protein and lipid composition and serve as hubs for inter-organelle communication and signaling. Despite extensive investigation of MCS protein composition and functional roles, little is known about the process of MCS formation. In this perspective, we propose a hypothesis that MCS are formed not as a result of random interactions between membranes of ER and other organelles but on the basis of pre-existing cholesterol-enriched ER microdomains.

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Crucial Players for Inter-Organelle Communication: PI5P4Ks and Their Lipid Product PI-4,5-P2 Come to the Surface

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.791758 ◽

2022 ◽

Vol 9 ◽

Author(s):

Archna Ravi ◽

Lavinia Palamiuc ◽

Brooke M. Emerling

Keyword(s):

Stress Response ◽

Human Diseases ◽

Type Ii ◽

Metabolic Homeostasis ◽

Cellular Homeostasis ◽

Evolutionarily Conserved ◽

Lipid Product ◽

Canonical Type ◽

Organelle Communication ◽

A Minor

While organelles are individual compartments with specialized functions, it is becoming clear that organellar communication is essential for maintaining cellular homeostasis. This cooperation is carried out by various interactions taking place on the membranes of organelles. The membranes themselves contain a multitude of proteins and lipids that mediate these connections and one such class of molecules facilitating these relations are the phospholipids. There are several phospholipids, but the focus of this perspective is on a minor group called the phosphoinositides and specifically, phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2). This phosphoinositide, on intracellular membranes, is largely generated by the non-canonical Type II PIPKs, namely, Phosphotidylinositol-5-phosphate-4-kinases (PI5P4Ks). These evolutionarily conserved enzymes are emerging as key stress response players in cells. Further, PI5P4Ks have been shown to modulate pathways by regulating organelle crosstalk, revealing roles in preserving metabolic homeostasis. Here we will attempt to summarize the functions of the PI5P4Ks and their product PI-4,5-P2 in facilitating inter-organelle communication and how they impact cellular health as well as their relevance to human diseases.

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Enzyme-Instructed Assemblies Enable Mitochondria Localization of Histone H2B in Cancer Cells

10.26434/chemrxiv.11362508.v1 ◽

2019 ◽

Author(s):

Hongjian He ◽

Jiaqi Guo ◽

Xingyi Lin ◽

Bing Xu

Keyword(s):

Cancer Cells ◽

Aspartic Acid ◽

Self Assembly ◽

Nuclear Protein ◽

Subcellular Organelles ◽

Cellular Behaviors ◽

Nuclear Location ◽

Endogenous Proteins ◽

Cleavable Peptide ◽

Organelle Communication

<p>It is known that a highly dynamic communication among subcellular organelles (e.g., cytosol, endoplasmic reticulum (ER), mitochondria, and nucleus) dictate cellular behaviors. But little information exists on how the inter-organelle crosstalk impacts cancer cells due to the lack of approaches that manipulate inter-organelle communication in cancer cells. We unexpectedly found that a negatively charged, enzyme cleavable peptide enables the trafficking of histone protein (H2B), a nuclear protein, to the mitochondria in cancer cells. The peptide, denoted as MitoFlag, interacts with the nuclear location sequence (NLS) of H2B to block it entering nucleus. A protease on the mitochondria cleaves the Flag from the complex of MitoFlag and H2B to form assemblies that retain H2B on the mitochondria and facilitate the H2B entering mitochondria. Molecular validation of MitoFlag shows that adding NLS, replacing aspartic acid residues by glutamic acid residues, or changing L-aspartic acid to D-aspartic residue abolishes the trafficking of H2B into mitochondria of HeLa cells. As the first example of enzyme-instructed self-assembly (EISA) of a synthetic peptide for trafficking endogenous proteins, this work provides insights for understanding and manipulating inter-organelle communication in cells.</p>

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Organelle communication: Signaling crossroads between homeostasis and disease

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2014.01.019 ◽

2014 ◽

Vol 50 ◽

pp. 55-59 ◽

Cited By ~ 25

Author(s):

Roberto Bravo-Sagua ◽

Natalia Torrealba ◽

Felipe Paredes ◽

Pablo E. Morales ◽

Christian Pennanen ◽

...

Keyword(s):

Organelle Communication

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Cellular Aging Characteristics and Their Association with Age-Related Disorders

Antioxidants ◽

10.3390/antiox9020094 ◽

2020 ◽

Vol 9 (2) ◽

pp. 94 ◽

Cited By ~ 8

Author(s):

Magdalena Rudzińska ◽

Alessandro Parodi ◽

Anastasia V. Balakireva ◽

Olga E. Chepikova ◽

Franco M. Venanzi ◽

...

Keyword(s):

Oxidative Stress ◽

Cellular Senescence ◽

Current Knowledge ◽

Cell Metabolism ◽

Critical Role ◽

Cellular Aging ◽

Molecular Signaling ◽

Age Related ◽

Organelle Communication ◽

Metabolic Dysfunctions

Different molecular signaling pathways, biological processes, and intercellular communication mechanisms control longevity and are affected during cellular senescence. Recent data have suggested that organelle communication, as well as genomic and metabolic dysfunctions, contribute to this phenomenon. Oxidative stress plays a critical role by inducing structural modifications to biological molecules while affecting their function and catabolism and eventually contributing to the onset of age-related dysfunctions. In this scenario, proteins are not adequately degraded and accumulate in the cell cytoplasm as toxic aggregates, increasing cell senescence progression. In particular, carbonylation, defined as a chemical reaction that covalently and irreversibly modifies proteins with carbonyl groups, is considered to be a significant indicator of protein oxidative stress and aging. Here, we emphasize the role and dysregulation of the molecular pathways controlling cell metabolism and proteostasis, the complexity of the mechanisms that occur during aging, and their association with various age-related disorders. The last segment of the review details current knowledge on protein carbonylation as a biomarker of cellular senescence in the development of diagnostics and therapeutics for age-related dysfunctions.

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Endosomal and Phagosomal SNAREs

Physiological Reviews ◽

10.1152/physrev.00037.2017 ◽

2018 ◽

Vol 98 (3) ◽

pp. 1465-1492 ◽

Cited By ~ 21

Author(s):

Ilse Dingjan ◽

Peter T. A. Linders ◽

Danielle R. J. Verboogen ◽

Natalia H. Revelo ◽

Martin ter Beest ◽

...

Keyword(s):

Intracellular Transport ◽

Snare Proteins ◽

Intracellular Pathogens ◽

Snare Protein ◽

Attachment Protein ◽

System A ◽

Protein Receptor ◽

Sensitive Factor ◽

Organelle Communication ◽

Factor Attachment Protein Receptor

The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein family is of vital importance for organelle communication. The complexing of cognate SNARE members present in both the donor and target organellar membranes drives the membrane fusion required for intracellular transport. In the endocytic route, SNARE proteins mediate trafficking between endosomes and phagosomes with other endosomes, lysosomes, the Golgi apparatus, the plasma membrane, and the endoplasmic reticulum. The goal of this review is to provide an overview of the SNAREs involved in endosomal and phagosomal trafficking. Of the 38 SNAREs present in humans, 30 have been identified at endosomes and/or phagosomes. Many of these SNAREs are targeted by viruses and intracellular pathogens, which thereby reroute intracellular transport for gaining access to nutrients, preventing their degradation, and avoiding their detection by the immune system. A fascinating picture is emerging of a complex transport network with multiple SNAREs being involved in consecutive trafficking routes.

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Editorial overview: Cell organelles: Organelle communication: new means and new views

Current Opinion in Cell Biology ◽

10.1016/j.ceb.2015.07.008 ◽

2015 ◽

Vol 35 ◽

pp. v-vi

Author(s):

Maya Schuldiner ◽

Wei Guo

Keyword(s):

Cell Organelles ◽

Organelle Communication

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Enzyme-Instructed Assemblies Enable Mitochondria Localization of Histone H2B in Cancer Cells

10.26434/chemrxiv.11362508 ◽

2019 ◽

Author(s):

Hongjian He ◽

Jiaqi Guo ◽

Xingyi Lin ◽

Bing Xu

Keyword(s):

Cancer Cells ◽

Aspartic Acid ◽

Self Assembly ◽

Nuclear Protein ◽

Subcellular Organelles ◽

Cellular Behaviors ◽

Nuclear Location ◽

Endogenous Proteins ◽

Cleavable Peptide ◽

Organelle Communication

<p>It is known that a highly dynamic communication among subcellular organelles (e.g., cytosol, endoplasmic reticulum (ER), mitochondria, and nucleus) dictate cellular behaviors. But little information exists on how the inter-organelle crosstalk impacts cancer cells due to the lack of approaches that manipulate inter-organelle communication in cancer cells. We unexpectedly found that a negatively charged, enzyme cleavable peptide enables the trafficking of histone protein (H2B), a nuclear protein, to the mitochondria in cancer cells. The peptide, denoted as MitoFlag, interacts with the nuclear location sequence (NLS) of H2B to block it entering nucleus. A protease on the mitochondria cleaves the Flag from the complex of MitoFlag and H2B to form assemblies that retain H2B on the mitochondria and facilitate the H2B entering mitochondria. Molecular validation of MitoFlag shows that adding NLS, replacing aspartic acid residues by glutamic acid residues, or changing L-aspartic acid to D-aspartic residue abolishes the trafficking of H2B into mitochondria of HeLa cells. As the first example of enzyme-instructed self-assembly (EISA) of a synthetic peptide for trafficking endogenous proteins, this work provides insights for understanding and manipulating inter-organelle communication in cells.</p>

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A plastid two-pore channel essential for inter-organelle communication and growth of Toxoplasma gondii

Nature Communications ◽

10.1038/s41467-021-25987-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhu-Hong Li ◽

Thayer P. King ◽

Lawrence Ayong ◽

Beejan Asady ◽

Xinjiang Cai ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Lytic Cycle ◽

Site Formation ◽

Pore Channel ◽

Apicomplexan Parasites ◽

Unicellular Organisms ◽

Membrane Contact ◽

Organelle Communication ◽

Acidic Organelles ◽

Pore Lining

AbstractTwo-pore channels (TPCs) are a ubiquitous family of cation channels that localize to acidic organelles in animals and plants to regulate numerous Ca2+-dependent events. Little is known about TPCs in unicellular organisms despite their ancient origins. Here, we characterize a TPC from Toxoplasma gondii, the causative agent of toxoplasmosis. TgTPC is a member of a novel clad of TPCs in Apicomplexa, distinct from previously identified TPCs and only present in coccidians. We show that TgTPC localizes not to acidic organelles but to the apicoplast, a non-photosynthetic plastid found in most apicomplexan parasites. Conditional silencing of TgTPC resulted in progressive loss of apicoplast integrity, severely affecting growth and the lytic cycle. Isolation of TPC null mutants revealed a selective role for TPCs in replication independent of apicoplast loss that required conserved residues within the pore-lining region. Using a genetically-encoded Ca2+ indicator targeted to the apicoplast, we show that Ca2+ signals deriving from the ER but not from the extracellular space are selectively transmitted to the lumen. Deletion of the TgTPC gene caused reduced apicoplast Ca2+ uptake and membrane contact site formation between the apicoplast and the ER. Fundamental roles for TPCs in maintaining organelle integrity, inter-organelle communication and growth emerge.

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Regulation of the ER stress response by a mitochondrial microprotein

Nature Communications ◽

10.1038/s41467-019-12816-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 24

Author(s):

Qian Chu ◽

Thomas F. Martinez ◽

Sammy Weiser Novak ◽

Cynthia J. Donaldson ◽

Dan Tan ◽

...

Keyword(s):

Mitochondrial Protein ◽

Mitochondrial Outer Membrane ◽

Unfolded Proteins ◽

Functional Studies ◽

Unfolded Protein ◽

Er Stress Response ◽

Organelle Communication ◽

The Unfolded Protein Response ◽

Protein Response

Abstract Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER–mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an undiscovered role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.

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