Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions

Humer, Christina; Romanin, Christoph; Höglinger, Carmen

doi:10.3390/cells11030371

Cited by 3 publications

(3 citation statements)

References 182 publications

(336 reference statements)

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“…Thus, SOCE might be activated by pUS21-dependent ER Ca 2+ depletion. To address this question experimentally, random cell migration assays were performed in the presence of BTP2, a specific inhibitor of SOCE ( 28 ) that did not alter the expression of pUS21-HA in induced T-REx-U2OS-US21-HA cells ( Fig. S3 ).…”

Section: Resultsmentioning

confidence: 99%

The US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion

Luganini

Serra

Scarpellino

et al. 2023

mBio

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The human cytomegalovirus (HCMV) US12 gene family contributes to virus-host interactions by regulating the virus’ cell tropism and its evasion of host innate immune responses. US21, one of the 10 US12 genes (US12–US21), is a descendant of a captured cellular transmembrane BAX inhibitor motif-containing gene. It encodes a 7TMD endoplasmic reticulum (ER)-resident viroporin (pUS21) capable of reducing the Ca 2+ content of ER stores, which, in turn, protects cells against apoptosis. Since regulation of Ca 2+ homeostasis affects a broad range of cellular responses, including cell motility, we investigated whether pUS21 might also interfere with this cytobiological consequence of Ca 2+ signaling. Indeed, deletion of the US21 gene impaired the ability of HCMV-infected cells to migrate, whereas expression of US21 protein stimulated cell migration and adhesion, as well as focal adhesion (FA) dynamics, in a way that depended on its ability to manipulate ER Ca 2+ content. Mechanistic studies revealed pUS21-mediated cell migration to involve calpain 2 activation since its inhibition prevented the viroporin’s effects on cell motility. Pertinently, pUS21 expression stimulated a store-operated Ca 2+ entry (SOCE) mechanism that may determine the activation of calpain 2 by promoting Ca 2+ entry. Furthermore, pUS21 was observed to interact with talin-1, a calpain 2 substrate, and crucial protein component of FA complexes. A functional consequence of this interaction was confirmed by talin-1 knockdown, which abrogated the pUS21-mediated increase in cell migration. Together, these results indicate the US21-encoded viroporin to be a viral regulator of cell adhesion and migration in the context of HCMV infection. IMPORTANCE Human cytomegalovirus (HCMV) is an opportunistic pathogen that owes part of its success to the capture, duplication, and tuning of cellular genes to generate modern viral proteins which promote infection and persistence in the host by interfering with many cell biochemical and physiological pathways. The US21 viral protein provides an example of this evolutionary strategy: it is a cellular-derived calcium channel that manipulates intracellular calcium homeostasis to confer edges to HCMV replication. Here, we report on the characterization of a novel function of the US21 protein as a viral regulator of cell migration and adhesion through mechanisms involving its calcium channel activity. Characterization of HCMV multifunctional regulatory proteins, like US21, supports the better understanding of viral pathogenesis and may open avenues for the design of new antiviral strategies that exploit their functions.

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Section: Resultsmentioning

confidence: 99%

The US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion

Luganini

Serra

Scarpellino

et al. 2023

mBio

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“…This ensures cell type-specific regulation by CRAC channels and is relevant in the development of diseases [ 121 , 122 , 140 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 ]. Their activation mechanisms have been summarized in detail in previous reviews [ 9 , 32 , 154 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 ]. In the following paragraphs, only the most important activation steps and mechanisms necessary for understanding the following chapters on the application of synthetic biology tools to the CRAC components STIM1 and Orai1 are briefly described.…”

Section: Crac Channel Working Mechanismsmentioning

confidence: 99%

Synthetic Biology Meets Ca2+ Release-Activated Ca2+ Channel-Dependent Immunomodulation

Bacsa,

Hopl,

Derler

2024

Cells

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Many essential biological processes are triggered by the proximity of molecules. Meanwhile, diverse approaches in synthetic biology, such as new biological parts or engineered cells, have opened up avenues to precisely control the proximity of molecules and eventually downstream signaling processes. This also applies to a main Ca2+ entry pathway into the cell, the so-called Ca2+ release-activated Ca2+ (CRAC) channel. CRAC channels are among other channels are essential in the immune response and are activated by receptor–ligand binding at the cell membrane. The latter initiates a signaling cascade within the cell, which finally triggers the coupling of the two key molecular components of the CRAC channel, namely the stromal interaction molecule, STIM, in the ER membrane and the plasma membrane Ca2+ ion channel, Orai. Ca2+ entry, established via STIM/Orai coupling, is essential for various immune cell functions, including cytokine release, proliferation, and cytotoxicity. In this review, we summarize the tools of synthetic biology that have been used so far to achieve precise control over the CRAC channel pathway and thus over downstream signaling events related to the immune response.

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“…Orai1 C-termini is considered the primary binding site with STIM1, as deletion of this fragment completely abolishes the association between STIM1-Orai1 [ 33 , 41 , 42 ]. Although still a matter of debate (extensively discussed in [ 43 ]), several reports have demonstrated that STIM1 interacts with Orai1 N-termini to gate and modulate the opened Orai1 channel [ 26 , 34 , 44 , 45 ]. For instance, a recent study has shown that the STIM1-Orai1 N-termini interaction is vital to obtain CRAC currents featuring the hallmarks of a wild-type CRAC current [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

Similarities and Differences between the Orai1 Variants: Orai1α and Orai1β

Jardín

Berna‐Erro

Nieto‐Felipe

et al. 2022

IJMS

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Orai1, the first identified member of the Orai protein family, is ubiquitously expressed in the animal kingdom. Orai1 was initially characterized as the channel responsible for the store-operated calcium entry (SOCE), a major mechanism that allows cytosolic calcium concentration increments upon receptor-mediated IP3 generation, which results in intracellular Ca2+ store depletion. Furthermore, current evidence supports that abnormal Orai1 expression or function underlies several disorders. Orai1 is, together with STIM1, the key element of SOCE, conducting the Ca2+ release-activated Ca2+ (CRAC) current and, in association with TRPC1, the store-operated Ca2+ (SOC) current. Additionally, Orai1 is involved in non-capacitative pathways, as the arachidonate-regulated or LTC4-regulated Ca2+ channel (ARC/LRC), store-independent Ca2+ influx activated by the secretory pathway Ca2+-ATPase (SPCA2) and the small conductance Ca2+-activated K+ channel 3 (SK3). Furthermore, Orai1 possesses two variants, Orai1α and Orai1β, the latter lacking 63 amino acids in the N-terminus as compared to the full-length Orai1α form, which confers distinct features to each variant. Here, we review the current knowledge about the differences between Orai1α and Orai1β, the implications of the Ca2+ signals triggered by each variant, and their downstream modulatory effect within the cell.

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Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions

Cited by 3 publications

References 182 publications

The US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion

The US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion

Synthetic Biology Meets Ca2+ Release-Activated Ca2+ Channel-Dependent Immunomodulation

Similarities and Differences between the Orai1 Variants: Orai1α and Orai1β

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