AP-1/σ1A and AP-1/σ1B adaptor-proteins differentially regulate neuronal early endosome maturation via the Rab5/Vps34-pathway

Abstract Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of E. coli. In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases.

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PxdA interacts with the DipA phosphatase to regulate endosomal hitchhiking of peroxisomes

Molecular Biology of the Cell ◽

10.1091/mbc.e20-08-0559 ◽

2021 ◽

pp. mbc.E20-08-0559

Author(s):

John Salogiannis ◽

Jenna R. Christensen ◽

Livia D. Songster ◽

Adriana Aguilar-Maldonado ◽

Nandini Shukla ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Lipid Droplets ◽

Molecular Mechanisms ◽

Ustilago Maydis ◽

Adaptor Proteins ◽

Early Endosome ◽

Alternative Mode ◽

Ribonucleoprotein Complexes ◽

Early Endosomes ◽

Mode Of Transport

In canonical microtubule-based transport, adaptor proteins link cargos to dynein and kinesin motors. Recently, an alternative mode of transport known as ‘hitchhiking’ was discovered, where cargos achieve motility by hitching a ride on already-motile cargos, rather than attaching to a motor protein. Hitchhiking has been best-studied in two filamentous fungi, Aspergillus nidulans and Ustilago maydis. In U. maydis, ribonucleoprotein complexes, peroxisomes, lipid droplets, and endoplasmic reticulum hitchhike on early endosomes. In A. nidulans, peroxisomes hitchhike using a putative molecular linker, PxdA, which associates with early endosomes. However, whether other organelles use PxdA to hitchhike on early endosomes is unclear, as are the molecular mechanisms that regulate hitchhiking. Here we find that the proper distribution of lipid droplets, mitochondria and pre-autophagosomes do not require PxdA, suggesting that PxdA is a peroxisome-specific molecular linker. We identify two new pxdA alleles, including a point mutation (R2044P) that disrupts PxdA's ability to associate with early endosomes and reduces peroxisome movement. We also identify a novel regulator of peroxisome hitchhiking, the phosphatase DipA. DipA co-localizes with early endosomes and its early endosome-association relies on PxdA. Together, our data suggest that PxdA and the DipA phosphatase are specific regulators of peroxisome hitchhiking on early endosomes. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Early endosomes and endosomal coatomer are required for autophagy

The Journal of Cell Biology ◽

10.1083/jcb.200810098 ◽

2009 ◽

Vol 185 (2) ◽

pp. 305-321 ◽

Cited By ~ 188

Author(s):

Minoo Razi ◽

Edmond Y.W. Chan ◽

Sharon A. Tooze

Keyword(s):

Early Endosome ◽

Autophagic Flux ◽

Loss Of Function ◽

Ubiquitinated Proteins ◽

Golgi Transport ◽

Late Endosomes ◽

Early Endosomes ◽

Endosomal Pathway ◽

Endosome Maturation ◽

Autophagy Inhibition

Autophagy, an intracellular degradative pathway, maintains cell homeostasis under normal and stress conditions. Nascent double-membrane autophagosomes sequester and enclose cytosolic components and organelles, and subsequently fuse with the endosomal pathway allowing content degradation. Autophagy requires fusion of autophagosomes with late endosomes, but it is not known if fusion with early endosomes is essential. We show that fusion of AVs with functional early endosomes is required for autophagy. Inhibition of early endosome function by loss of COPI subunits (β′, β, or α) results in accumulation of autophagosomes, but not an increased autophagic flux. COPI is required for ER-Golgi transport and early endosome maturation. Although loss of COPI results in the fragmentation of the Golgi, this does not induce the formation of autophagosomes. Loss of COPI causes defects in early endosome function, as both transferrin recycling and EGF internalization and degradation are impaired, and this loss of function causes an inhibition of autophagy, an accumulation of p62/SQSTM-1, and ubiquitinated proteins in autophagosomes.

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SMAP2, a Novel ARF GTPase-activating Protein, Interacts with Clathrin and Clathrin Assembly Protein and Functions on the AP-1–positive Early Endosome/Trans-Golgi Network

Molecular Biology of the Cell ◽

10.1091/mbc.e05-10-0909 ◽

2006 ◽

Vol 17 (6) ◽

pp. 2592-2603 ◽

Cited By ~ 51

Author(s):

Waka Natsume ◽

Kenji Tanabe ◽

Shunsuke Kon ◽

Naomi Yoshida ◽

Toshio Watanabe ◽

...

Keyword(s):

Brefeldin A ◽

Adaptor Proteins ◽

Early Endosome ◽

Dependent Manner ◽

Transferrin Receptors ◽

Gtpase Activating Protein ◽

Trans Golgi Network ◽

Early Endosomes ◽

Golgi Network

We recently reported that SMAP1, a GTPase-activating protein (GAP) for Arf6, directly interacts with clathrin and regulates the clathrin-dependent endocytosis of transferrin receptors from the plasma membrane. Here, we identified a SMAP1 homologue that we named SMAP2. Like SMAP1, SMAP2 exhibits GAP activity and interacts with clathrin heavy chain (CHC). Furthermore, we show that SMAP2 interacts with the clathrin assembly protein CALM. Unlike SMAP1, however, SMAP2 appears to be a regulator of Arf1 in vivo, because cells transfected with a GAP-negative SMAP2 mutant were resistant to brefeldin A. SMAP2 colocalized with the adaptor proteins for clathrin AP-1 and EpsinR on the early endosomes/trans-Golgi-network (TGN). Moreover, overexpression of SMAP2 delayed the accumulation of TGN38/46 molecule on the TGN. This suggests that SMAP2 functions in the retrograde, early endosome-to-TGN pathway in a clathrin- and AP-1–dependent manner. Thus, the SMAP gene family constitutes an important ArfGAP subfamily, with each SMAP member exerting both common and distinct functions in vesicle trafficking.

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PxdA interacts with the DipA phosphatase to regulate endosomal hitchhiking of peroxisomes

10.1101/2020.02.03.932616 ◽

2020 ◽

Author(s):

John Salogiannis ◽

Jenna R. Christensen ◽

Adriana Aguilar-Maldonado ◽

Nandini Shukla ◽

Samara L. Reck-Peterson

Keyword(s):

Molecular Motors ◽

Lipid Droplets ◽

Molecular Mechanisms ◽

Ustilago Maydis ◽

Adaptor Proteins ◽

Early Endosome ◽

Alternative Mode ◽

Ribonucleoprotein Complexes ◽

Early Endosomes ◽

Mode Of Transport

AbstractIn canonical microtubule-based transport, adaptor proteins link cargos to the molecular motors dynein and kinesin. Recently, an alternative mode of transport known as ‘hitchhiking’ was discovered, in which a cargo achieves motility by hitching a ride on an already-motile cargo, rather than attaching to a motor protein. Hitchhiking has been best-studied in two filamentous fungi, Aspergillus nidulans and Ustilago maydis. In U. maydis, ribonucleoprotein complexes, peroxisomes, lipid droplets, and endoplasmic reticulum all hitchhike on early endosomes. In A. nidulans, peroxisomes hitchhike using a putative molecular linker, PxdA, that associates with early endosomes. However, whether other organelles use PxdA to hitchhike on early endosomes is unclear, as are the molecular mechanisms that regulate hitchhiking in A. nidulans. Here we find that the proper distribution of lipid droplets, mitochondria and autophagosomes do not require PxdA, suggesting that PxdA is a molecular linker specific to peroxisomes. We also identify two new pxdA alleles, including a point mutation (R2044P) that disrupts PxdA’s ability to associate with early endosomes and reduces peroxisome movement. Finally, we identify a novel regulator of peroxisome hitchhiking, the phosphatase DipA. DipA co-localizes with early endosomes and its early endosome-association relies on PxdA.

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Host factors in virus budding ? Insights from yeast

Microbiology Australia ◽

10.1071/ma07059 ◽

2007 ◽

Vol 28 (2) ◽

pp. 59

Author(s):

Parimala R Vajjhala ◽

Alan L Munn

Keyword(s):

Mammalian Cells ◽

Multivesicular Body ◽

Early Endosome ◽

Yeast Saccharomyces Cerevisiae ◽

Enveloped Viruses ◽

Cellular Processes ◽

B Virus ◽

Immunodeficiency Virus ◽

Membrane Bound ◽

Endosome Maturation

The budding yeast, Saccharomyces cerevisiae, is an excellentmodel organism for the study of eukaryotic cellular processes such as endocytosis 1. Like other eukaryotic cells, yeast take up extracellular material by invagination of the plasma membraneto form a vesicle. The internalised material is transported to a membrane-bound compartment, the early endosome. As the early endosome matures, internal vesicles form within the lumen giving it the appearance of a multivesicular body (vesicles enclosed by a membrane). The machinery required for endosome maturation is highly conserved between yeast and mammalian cells. In mammalian cells this machinery is also required for the budding of enveloped viruses. Here we discuss how studies of endosome maturation in S. cerevisiae have given valuable insights into the mechanism by which clinically important enveloped viruses, including human immunodeficiency virus (HIV) and hepatitis B virus, are released from mammalian cells.

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