scholarly journals A Role of the Lowe Syndrome Protein OCRL in Early Steps of the Endocytic Pathway

2007 ◽  
Vol 13 (3) ◽  
pp. 377-390 ◽  
Author(s):  
Kai S. Erdmann ◽  
Yuxin Mao ◽  
Heather J. McCrea ◽  
Roberto Zoncu ◽  
Sangyoon Lee ◽  
...  
Keyword(s):  
Endocytic Pathway ◽  
Lowe Syndrome ◽  
Syndrome Protein

The role of the Lowe syndrome protein OCRL in the endocytic pathway

2015 ◽  
Vol 396 (12) ◽  
pp. 1293-1300 ◽  
Author(s):  
Shruti Sharma ◽  
Agnieszka Skowronek ◽  
Kai Sven Erdmann
Keyword(s):  
Genetic Disorders ◽  
Endocytic Pathway ◽  
Lowe Syndrome ◽  
Coated Pits ◽  
Golgi Network ◽  
Endocytic Compartments ◽  
Syndrome Protein

Abstract Mutations of the inositol-5-phosphatase OCRL cause Lowe syndrome and Dent-II disease. Both are rare genetic disorders characterized by renal defects. Lowe syndrome is furthermore characterized by defects of the eye (congenital cataracts) and nervous system (mental disabilities, hypotonia). OCRL has been localised to various endocytic compartments suggesting impairments in the endocytic pathway as possible disease mechanism. Recent evidence strongly supports this view and shows essential roles of OCRL at clathrin coated pits, transport of cargo from endosomes to the trans-Golgi network as well as recycling of receptors from endosomes to the plasma membrane. In particular in vitro and in vivo evidence demonstrates an important role of OCRL in recycling of megalin, a multi-ligand receptor crucial for reabsorption of nutrients in the proximal tubulus, a process severely impaired in Lowe syndrome patients. Thus defects in the endocytic pathway are likely to significantly contribute to the kidney phenotype in Lowe syndrome and Dent-II disease.

scholarly journals The Cellular and Physiological Functions of the Lowe Syndrome Protein OCRL1

Traffic ◽  
2014 ◽  
Vol 15 (5) ◽  
pp. 471-487 ◽  
Author(s):  
Zenobia B. Mehta ◽  
Grzegorz Pietka ◽  
Martin Lowe
Keyword(s):  
Lowe Syndrome ◽  
Physiological Functions ◽  
Syndrome Protein

scholarly journals A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

2019 ◽  
Author(s):  
Samuel J. Dobson ◽  
Jamel Mankouri ◽  
Adrian Whitehouse
Keyword(s):  
Ion Channels ◽  
Broad Spectrum ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Asymptomatic Infection ◽  
Endocytic Pathway ◽  
Endosomal Trafficking ◽  
Nuclear Entry ◽  
Novel Target

ABSTRACTFollowing internalisation viruses have to escape the endocytic pathway and deliver their genomes to initiate replication. Members of the Polyomaviridae transit through the endolysosomal network and through the endoplasmic reticulum (ER), from which heavily degraded capsids escape into the cytoplasm prior to nuclear entry. Acidification of endosomes and ER entry are essential in the lifecycle of polyomaviruses, however many mechanistic requirements are yet to be elucidated. Alteration of endocytic pH relies upon the activity of ion channels. Using two polyomaviruses with differing capsid architecture, namely Simian virus 40 (SV40) and Merkel cell polyomavirus (MCPyV), we firstly describe methods to rapidly quantify infection using an IncuCyte ZOOM instrument, prior to investigating the role of K+ and Ca2+ channels during early stages of infection. Broad spectrum inhibitors identified that MCPyV, but not SV40, is sensitive to K+ channel modulation. In contrast, both viruses are restricted by the broad spectrum Ca2+ channel inhibitor verapamil, however specific targeting of transient or long lasting Ca2+ channel subfamilies had no detrimental effect. Further investigation revealed that tetrandrine blockage of two-pore channels (TPCs), the activity of which is essential for endolysosomal-ER fusion, ablates infectivity of both MCPyV and SV40 by preventing disassembly of the capsid, which is required for the exposure of minor capsid protein nuclear signals necessary for nuclear transport. This study therefore identifies a novel target to restrict the entry of polyomaviruses.IMPORTANCEPolyomaviruses establish ubiquitous, asymptomatic infection in their host. However, in the immunocompromised these viruses can cause a range of potentially fatal diseases. Through the use of SV40 and MCPyV, two polyomaviruses with different capsid organisation, we have investigated the role of ion channels during infection. Here, we show that Ca2+ channel activity is essential for both polyomaviruses and that MCPyV is also sensitive to K+ channel blockage, highlighting new mechanistic requirements of ion channels during polyomavirus infection. In particular, tetrandrine blockage of endolysosomal-ER fusion is highlighted as an essential modulator of both SV40 and MCPyV. Given that the role of ion channels in disease have been well characterised, there is a large panel of clinically available therapeutics that could be repurposed to restrict persistent polyomavirus infection and may ultimately prevent polyomavirus-associated disease.

HIV infection of fetal human astrocytes: the potential role of a receptor-mediated endocytic pathway

1999 ◽  
Vol 823 (1-2) ◽  
pp. 24-32 ◽  
Author(s):  
Hsiao-Nan Hao ◽  
William D Lyman
Keyword(s):  
Hiv Infection ◽  
Potential Role ◽  
Endocytic Pathway ◽  
Human Astrocytes

scholarly journals Epidermal Growth Factor Receptor and Abl2 Kinase Regulate Distinct Steps of Human Papillomavirus 16 Endocytosis

2020 ◽  
Vol 94 (11) ◽  
Author(s):  
Carina Bannach ◽  
Pia Brinkert ◽  
Lena Kühling ◽  
Lilo Greune ◽  
M. Alexander Schmidt ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Endocytic Pathway ◽  
Egfr Signaling ◽  
Endocytic Vesicle ◽  
Human Papillomavirus 16 ◽  
Epidermal Growth

ABSTRACT Human papillomavirus 16 (HPV16), the leading cause of cervical cancer, exploits a novel endocytic pathway during host cell entry. This mechanism shares many requirements with macropinocytosis but differs in the mode of vesicle formation. Previous work indicated a role of the epidermal growth factor receptor (EGFR) in HPV16 endocytosis. However, the functional outcome of EGFR signaling and its downstream targets during HPV16 uptake are not well characterized. Here, we analyzed the functional importance of signal transduction via EGFR and its downstream effectors for endocytosis of HPV16. Our findings indicate two phases of EGFR signaling as follows: a—likely dispensable—transient activation with or shortly after cell binding and signaling required throughout the process of asynchronous internalization of HPV16. Interestingly, EGFR inhibition interfered with virus internalization and strongly reduced the number of endocytic pits, suggesting a role for EGFR signaling in the induction of HPV16 endocytosis. Moreover, we identified the Src-related kinase Abl2 as a novel regulator of virus uptake. Inhibition of Abl2 resulted in an accumulation of misshaped endocytic pits, indicating Abl2’s importance for endocytic vesicle maturation. Since Abl2 rather than Src, a regulator of membrane ruffling during macropinocytosis, mediated downstream signaling of EGFR, we propose that the selective effector targeting downstream of EGFR determines whether HPV16 endocytosis or macropinocytosis is induced. IMPORTANCE Human papillomaviruses are small, nonenveloped DNA viruses that infect skin and mucosa. The so-called high-risk HPVs (e.g., HPV16, HPV18, HPV31) have transforming potential and are associated with various anogenital and oropharyngeal tumors. These viruses enter host cells by a novel endocytic pathway with unknown cellular function. To date, it is unclear how endocytic vesicle formation occurs mechanistically. Here, we addressed the role of epidermal growth factor receptor signaling, which has previously been implicated in HPV16 endocytosis and identified the kinase Abl2 as a novel regulator of virus uptake. Since other viruses, such as influenza A virus and lymphocytic choriomeningitis virus, possibly make use of related mechanisms, our findings shed light on fundamental strategies of virus entry and may in turn help to develop new host cell-targeted antiviral strategies.

scholarly journals Modulation of RAB7A Protein Expression Determines Resistance to Cisplatin through Late Endocytic Pathway Impairment and Extracellular Vesicular Secretion

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 52 ◽  
Author(s):  
Flora Guerra ◽  
Aurora Paiano ◽  
Danilo Migoni ◽  
Giulia Girolimetti ◽  
Anna Myriam Perrone ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Therapy Response ◽  
Endocytic Pathway ◽  
Endocytic Trafficking ◽  
Chemotherapy Response ◽  
Intracellular Accumulation ◽  
Human Patient ◽  
First Time ◽  
Vesicular Secretion

Background: Cisplatin (CDDP) is widely used in treatment of cancer, yet patients often develop resistance with consequent therapeutical failure. In CDDP-resistant cells alterations of endocytosis and lysosomal functionality have been revealed, although their causes and contribution to therapy response are unclear. Methods: We investigated the role of RAB7A, a key regulator of late endocytic trafficking, in CDDP-resistance by comparing resistant and sensitive cells using western blotting, confocal microscopy and real time PCR. Modulation of RAB7A expression was performed by transfection and RNA interference, while CDDP sensitivity and intracellular accumulation were evaluated by viability assays and chemical approaches, respectively. Also extracellular vesicles were purified and analyzed. Finally, correlations between RAB7A and chemotherapy response was investigated in human patient samples. Results: We demonstrated that down-regulation of RAB7A characterizes the chemoresistant phenotype, and that RAB7A depletion increases CDDP-resistance while RAB7A overexpression decreases it. In addition, increased production of extracellular vesicles is modulated by RAB7A expression levels and correlates with reduction of CDDP intracellular accumulation. Conclusions: We demonstrated, for the first time, that RAB7A regulates CDDP resistance determining alterations in late endocytic trafficking and drug efflux through extracellular vesicles.

A-kinase-anchoring proteins and cytoskeletal signalling events

2003 ◽  
Vol 31 (1) ◽  
pp. 87-89 ◽  
Author(s):  
J.D. Scott
Keyword(s):  
Protein Kinase ◽  
Molecular Mass ◽  
Protein Kinase A ◽  
Protein Kinases ◽  
Recent Progress ◽  
Membrane Receptors ◽  
Anchoring Proteins ◽  
Syndrome Protein ◽  
Kinase A

Targeting of protein kinases and phosphatases to the cytoskeleton enhances the regulation of many signalling events. Cytoskeletal signalling complexes facilitate this process by optimizing the relay of messages from membrane receptors to specific sites on the actin cytoskeleton. These signals influence fundamental cell properties such as shape, movement and division. Targeting of the cAMP-dependent kinase (protein kinase A) and other enzymes to this compartment is achieved through interaction with A-kinase-anchoring proteins (AKAPs). The present paper discusses recent progress on dissecting the biological role of WAVE1 (Wiskott–Alrich syndrome protein family verprolin homology protein 1), an AKAP that assembles a cytoskeletal transduction complex in response to signals that emanate from the low-molecular-mass GTPase, Rac.

scholarly journals Caveolae/raft-dependent endocytosis

2003 ◽  
Vol 161 (4) ◽  
pp. 673-677 ◽  
Author(s):  
Ivan R. Nabi ◽  
Phuong U. Le
Keyword(s):  
Endocytic Pathway ◽  
Regulatory Role ◽  
Cholesterol Depletion ◽  
Common Pathway ◽  
Caveolin 1 ◽  
Distinctive Morphology

Although caveolae are well-characterized subdomains of glycolipid rafts, their distinctive morphology and association with caveolins has led to their internalization being considered different from that of rafts. In this review, we propose that caveolae and rafts are internalized via a common pathway, caveolae/raft-dependent endocytosis, defined by its clathrin independence, dynamin dependence, and sensitivity to cholesterol depletion. The regulatory role of caveolin-1 and ligand sorting in this complex endocytic pathway are specifically addressed.

scholarly journals The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation

2016 ◽  
Vol 37 (3) ◽  
Author(s):  
Baomin Li ◽  
Sita Reddy ◽  
Lucio Comai
Keyword(s):  
Dna Polymerase ◽  
Werner Syndrome ◽  
Physiological Role ◽  
Cooperative Interaction ◽  
Strand Displacement ◽  
Winged Helix ◽  
Werner Syndrome Protein ◽  
Syndrome Protein ◽  
Lagging Strand

ABSTRACT The Werner syndrome protein (WRN) suppresses the loss of telomeres replicated by lagging-strand synthesis by a yet to be defined mechanism. Here, we show that whereas either WRN or the Bloom syndrome helicase (BLM) stimulates DNA polymerase δ progression across telomeric G-rich repeats, only WRN promotes sequential strand displacement synthesis and FEN1 cleavage, a critical step in Okazaki fragment maturation, at these sequences. Helicase activity, as well as the conserved winged-helix (WH) motif and the helicase and RNase D C-terminal (HRDC) domain play important but distinct roles in this process. Remarkably, WRN also influences the formation of FEN1 cleavage products during strand displacement on a nontelomeric substrate, suggesting that WRN recruitment and cooperative interaction with FEN1 during lagging-strand synthesis may serve to regulate sequential strand displacement and flap cleavage at other genomic sites. These findings define a biochemical context for the physiological role of WRN in maintaining genetic stability.

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