Calreticulin: one protein, one gene, many functions

The endoplasmic reticulum (ER) plays a critical role in the synthesis and chaperoning of membrane-associated and secreted proteins. The membrane is also an important site of Ca2+ storage and release. Calreticulin is a unique ER luminal resident protein. The protein affects many cellular functions, both in the ER lumen and outside of the ER environment. In the ER lumen, calreticulin performs two major functions: chaperoning and regulation of Ca2+ homoeostasis. Calreticulin is a highly versatile lectin-like chaperone, and it participates during the synthesis of a variety of molecules, including ion channels, surface receptors, integrins and transporters. The protein also affects intracellular Ca2+ homoeostasis by modulation of ER Ca2+ storage and transport. Studies on the cell biology of calreticulin revealed that the ER membrane is a very dynamic intracellular compartment affecting many aspects of cell physiology.

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Localization and quantification of endoplasmic reticulum Ca(2+)-ATPase isoform transcripts

AJP Cell Physiology ◽

10.1152/ajpcell.1995.269.3.c775 ◽

1995 ◽

Vol 269 (3) ◽

pp. C775-C784 ◽

Cited By ~ 244

Author(s):

K. D. Wu ◽

W. S. Lee ◽

J. Wey ◽

D. Bungard ◽

J. Lytton

Keyword(s):

Endoplasmic Reticulum ◽

Critical Role ◽

Qualitative Assessment ◽

Cell Physiology ◽

Striated Muscles ◽

Physiological Processes ◽

Alternatively Spliced ◽

Spleen Lymphocytes ◽

Fast Twitch ◽

In Cells

The Ca(2+)-adenosinetriphosphatase pump of the sarcoplasmic or endoplasmic reticulum (SERCA) plays a critical role in Ca2+ signaling and homeostasis in all cells and is encoded by a family of homologous and alternatively spliced genes. To understand more clearly the role the different isoforms play in cell physiology, we have undertaken a quantitative and qualitative assessment of the tissue distribution of transcripts encoding each SERCA isoform. SERCA1 expression is restricted to fast-twitch striated muscles, SERCA2a to cardiac and slow-twitch striated muscles, whereas SERCA2b is ubiquitously expressed. SERCA3 is expressed most abundantly in large and small intestine, thymus, and cerebellum and at lower levels in spleen, lymph node, and lung. In situ hybridization analyses revealed SERCA3 transcripts in cells of the intestinal crypt, the thymic cortex, and Purkinje cells in cerebellum. In addition, SERCA3 was expressed abundantly in isolated rat spleen lymphocytes, in various murine lymphoid cell lines, and in primary cultured microvascular endothelial cells. This analysis demonstrates that SERCA3 is expressed selectively in cells in which Ca2+ signaling plays a critical and sensitive role in regulating physiological processes.

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Phosphorylation of Eukaryotic Translation Initiation Factor 2α Coordinates rRNA Transcription and Translation Inhibition during Endoplasmic Reticulum Stress

Molecular and Cellular Biology ◽

10.1128/mcb.00260-09 ◽

2009 ◽

Vol 29 (15) ◽

pp. 4295-4307 ◽

Cited By ~ 65

Author(s):

Jenny B. DuRose ◽

Donalyn Scheuner ◽

Randal J. Kaufman ◽

Lawrence I. Rothblum ◽

Maho Niwa

Keyword(s):

Endoplasmic Reticulum ◽

Ribosome Biogenesis ◽

Critical Role ◽

Mammalian Target Of Rapamycin ◽

Protein Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Rrna Synthesis ◽

Cell Physiology ◽

Rrna Transcription

ABSTRACT The endoplasmic reticulum (ER) is the major cellular compartment where folding and maturation of secretory and membrane proteins take place. When protein folding needs exceed the capacity of the ER, the unfolded protein response (UPR) pathway modulates gene expression and downregulates protein translation to restore homeostasis. Here, we report that the UPR downregulates the synthesis of rRNA by inactivation of the RNA polymerase I basal transcription factor RRN3/TIF-IA. Inhibition of rRNA synthesis does not appear to involve the well-characterized mTOR (mammalian target of rapamycin) pathway; instead, PERK-dependent phosphorylation of eIF2α plays a critical role in the inactivation of RRN3/TIF-IA. Downregulation of rRNA transcription occurs simultaneously or slightly prior to eIF2α phosphorylation-induced translation repression. Since rRNA is the most abundant RNA species, constituting ∼90% of total cellular RNA, its downregulation exerts a significant impact on cell physiology. Our study demonstrates the first link between regulation of translation and rRNA synthesis with phosphorylation of eIF2α, suggesting that this pathway may be broadly utilized by stresses that activate eIF2α kinases in order to coordinately regulate translation and ribosome biogenesis during cellular stress.

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ER functions are exploited by viruses to support distinct stages of their life cycle

Biochemical Society Transactions ◽

10.1042/bst20200395 ◽

2020 ◽

Vol 48 (5) ◽

pp. 2173-2184

Author(s):

Yu-Jie Chen ◽

Parikshit Bagchi ◽

Billy Tsai

Keyword(s):

Endoplasmic Reticulum ◽

Protein Synthesis ◽

Life Cycle ◽

Ion Channels ◽

Calcium Homeostasis ◽

Life Cycles ◽

Therapeutic Approaches ◽

Cellular Functions ◽

Host Membrane ◽

Vast Network

The endoplasmic reticulum (ER), with its expansive membranous system and a vast network of chaperones, enzymes, sensors, and ion channels, orchestrates diverse cellular functions, ranging from protein synthesis, folding, secretion, and degradation to lipid biogenesis and calcium homeostasis. Strikingly, some of the functions of the ER are exploited by viruses to promote their life cycles. During entry, viruses must penetrate a host membrane and reach an intracellular destination to express and replicate their genomes. These events lead to the assembly of new viral progenies that exit the host cell, thereby initiating further rounds of infection. In this review, we highlight how three distinct viruses — polyomavirus, flavivirus, and coronavirus — co-opt key functions of the ER to cause infection. We anticipate that illuminating this virus-ER interplay will provide rational therapeutic approaches to combat the virus-induced diseases.

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Centrosomal P4.1-associated protein (CPAP) positively regulates endocytic vesicular transport and lysosome targeting of EGFR

Scientific Reports ◽

10.1038/s41598-021-91818-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Radhika Gudi ◽

Viswanathan Palanisamy ◽

Chenthamarakshan Vasu

Keyword(s):

Cell Surface ◽

Vesicular Transport ◽

Critical Role ◽

Cell Surface Receptor ◽

Regulatory Effect ◽

Cellular Functions ◽

Surface Receptors ◽

Egfr Activation ◽

Early Endosomes ◽

Surface Receptor

AbstractCentrosomal P4.1-associated protein (CPAP) plays a critical role in restricting the centriole length in human cells. Here, we report a novel, positive regulatory influence for CPAP on endocytic vesicular transport (EVT) and lysosome targeting of internalized-cell surface receptor EGFR. We observed that higher CPAP levels cause an increase in the abundance of multi-vesicular body (MVB) and EGFR is detectable in CPAP-overexpression induced puncta. The surface and cellular levels of EGFR are higher under CPAP deficiency and lower under CPAP overexpression. While ligand-engagement induced internalization or routing of EGFR into early endosomes is not influenced by cellular levels of CPAP, we found that targeting of ligand-activated, internalized EGFR to lysosome is impacted by CPAP levels. Transport of ligand-bound EGFR from early endosome to late endosome/MVB and lysosome is diminished in CPAP-depleted cells. Moreover, CPAP depleted cells appear to show a diminished ability to form MVB structures upon EGFR activation. These observations suggest a positive regulatory effect of CPAP on EVT of ligand-bound EGFR-like cell surface receptors to MVB and lysosome. Overall, identification of a non-centriolar function of CPAP in endocytic trafficking provides new insights in understanding the non-canonical cellular functions of CPAP.

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Tropomodulins and tropomyosins – organizers of cellular microcompartments

BioMolecular Concepts ◽

10.1515/bmc-2012-0037 ◽

2013 ◽

Vol 4 (1) ◽

pp. 89-101 ◽

Cited By ~ 3

Author(s):

Thomas Fath

Keyword(s):

Endoplasmic Reticulum ◽

Plasma Membrane ◽

Golgi Apparatus ◽

Critical Role ◽

Eukaryotic Cells ◽

Multigene Families ◽

Cellular Functions ◽

Cellular Morphogenesis ◽

Wide Range ◽

Associated Proteins

AbstractEukaryotic cells show a remarkable compartmentalization into compartments such as the cell nucleus, the Golgi apparatus, the endoplasmic reticulum, and endosomes. However, organelle structures are not the only means by which specialized compartments are formed. Recent research shows a critical role for diverse actin filament populations in defining functional compartments, here referred to as microcompartments, in a wide range of cells. These microcompartments are involved in regulating fundamental cellular functions including cell motility, plasma membrane organization, and cellular morphogenesis. In this overview, the importance of two multigene families of actin-associated proteins, tropomodulins and tropomyosins, their interactions with each other, and a large number of other proteins will be discussed in the context of generating specialized actin-based microcompartments.

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Redox regulation in the endoplasmic reticulum

Biochemical Society Transactions ◽

10.1042/bst20140065 ◽

2014 ◽

Vol 42 (4) ◽

pp. 905-908 ◽

Cited By ~ 11

Author(s):

Neil J. Bulleid ◽

Marcel van Lith

Keyword(s):

Endoplasmic Reticulum ◽

Protein Function ◽

Mammalian Cells ◽

Normal Cell ◽

Redox Regulation ◽

Redox Balance ◽

Secreted Proteins ◽

Cell Physiology ◽

Important Process ◽

Reductive Pathway

The efficient folding, assembly and secretion of proteins from mammalian cells is a critically important process for normal cell physiology. Breakdown of the ability of cells to secrete functional proteins leads to disease pathologies caused by a lack of protein function or by cell death resulting from an aggravated stress response. Central to the folding of secreted proteins is the formation of disulfides which both aid folding and provide stability to the protein structure. For disulfides to form correctly necessitates the appropriate redox environment within the endoplasmic reticulum: too reducing and disulfides will not form, too oxidizing and non-native disulfides will not be resolved. How the endoplasmic reticulum maintains the correct redox balance is unknown. Although we have a good appreciation of the processes leading to a more oxidizing environment, our understanding of how any counterbalancing reductive pathway operates is limited. The present review looks at potential mechanisms for introducing reducing equivalents into the endoplasmic reticulum and discusses an approach to test these hypotheses.

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Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System

International Journal of Molecular Sciences ◽

10.3390/ijms21165808 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5808

Author(s):

Cathleen Carlin ◽

Danny Manor

Keyword(s):

Cell Biology ◽

Host Response ◽

Dietary Cholesterol ◽

Cholesterol Homeostasis ◽

Cell Physiology ◽

Cellular Functions ◽

Cholesterol Trafficking ◽

Host Cell Proteins ◽

Regulatory Machinery ◽

Intracellular Pathway

In addition to providing invaluable insights to the host response to viral infection, adenovirus continues to be an important model system for discovering basic aspects of cell biology. This is especially true for products of early region three (E3), which have provided the foundation for understanding many new mechanisms regulating intracellular trafficking of host cell proteins involved in the host immune response. Cholesterol homeostasis is vital for proper cellular physiology, and disturbances in cholesterol balance are increasingly recognized as important factors in human disease. Despite its central role in numerous aspects of cellular functions, the mechanisms responsible for delivery of dietary cholesterol to the endoplasmic reticulum, where the lipid metabolic and regulatory machinery reside, remain poorly understood. In this review, we describe a novel intracellular pathway for cholesterol trafficking that has been co-opted by an adenovirus E3 gene product. We describe what is known about the molecular regulation of this pathway, how it might benefit viral replication, and its potential involvement in normal cell physiology. Finally, we make a case that adenovirus has co-opted a cellular pathway that may be dysregulated in various human diseases.

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How Viruses Use the VCP/p97 ATPase Molecular Machine

10.20944/preprints202108.0542.v1 ◽

2021 ◽

Author(s):

Poulami Das ◽

Jaquelin P. Dudley

Keyword(s):

Cell Biology ◽

Critical Role ◽

Host Protein ◽

Cellular Functions ◽

Aaa Atpase ◽

Virus Life Cycle ◽

Intracellular Parasites ◽

Viral Egress ◽

Wide Range

Viruses are obligate intracellular parasites that are dependent on host factors for their replication. One such host protein, p97 or the valosin-containing protein (VCP), is a highly conserved AAA ATPase that facilitates replication of diverse RNA- and DNA-containing viruses. The wide range of cellular functions attributed to this ATPase is consistent with its participation in multiple steps of the virus life cycle from entry and uncoating to viral egress. Studies of VCP/p97 interactions with viruses will provide important information about host processes and cell biology, but also viral strategies that take advantage of these host functions. The critical role of p97 in viral replication might be exploited as a target for development of pan-antiviral drugs that exceed the capability of virus-specific vaccines or therapeutics.

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