MINI REVIEW
published: 29 April 2020
doi: 10.3389/fimmu.2020.00739
Involvement of the TRPML Mucolipin
Channels in Viral Infections and
Anti-viral Innate Immune Responses
Giorgio Santoni 1* , Maria Beatrice Morelli 1 , Consuelo Amantini 2 , Massimo Nabissi 1 ,
Matteo Santoni 3 and Angela Santoni 4,5
1
Immunopathology Laboratory, School of Pharmacy, University of Camerino, Camerino, Italy, 2 Immunopathology
Laboratory, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy, 3 Medical Oncology
Unit, Hospital of Macerata, Macerata, Italy, 4 Department of Molecular Medicine, Sapienza University, Rome, Italy, 5 IRCCS
Neuromed, Pozzilli, Italy
Edited by:
Susanna Zierler,
Ludwig Maximilian University
of Munich, Germany
Reviewed by:
Christian Grimm,
Ludwig Maximilian University
of Munich, Germany
Kartik Venkatachalam,
University of Texas Health Science
Center at Houston, United States
*Correspondence:
Giorgio Santoni
giorgio.santoni@unicam.it
Specialty section:
This article was submitted to
Molecular Innate Immunity,
a section of the journal
Frontiers in Immunology
Received: 30 January 2020
Accepted: 31 March 2020
Published: 29 April 2020
Citation:
Santoni G, Morelli MB,
Amantini C, Nabissi M, Santoni M and
Santoni A (2020) Involvement of the
TRPML Mucolipin Channels in Viral
Infections and Anti-viral Innate
Immune Responses.
Front. Immunol. 11:739.
doi: 10.3389/fimmu.2020.00739
The TRPML channels (TRPML1, TRPML2, and TRPML3), belonging to the mucolipin
TRP subfamily, primary localize to a population of membrane-bonded vesicles along
the endocytosis, and exocytosis pathways. Human viruses enter host cells by plasma
membrane penetration or by receptor-mediated endocytosis. TRPML2 enhances the
infectivity of a number of enveloped viruses by promoting virus vesicular trafficking and
escape from endosomal compartment. TRPML2 expression is stimulated by interferon
and by several toll like receptor (TLR) activators, suggesting a possible role in the
activation of the innate immune response. Noteworthy, TRPML1 plays a major role in
single strand RNA/DNA trafficking into lysosomes and the lack of TRPML1 impairs the
TLR-7 and TLR-9 ligand transportation to lysosomes resulting in decreased dendritic
cell maturation/activation and migration to the lymph nodes. TRPML channels are also
expressed by natural killer (NK) cells, a subset of innate lymphocytes with an essential
role during viral infections; recent findings have indicated a role of TRPML1-mediated
modulation of secretory lysosomes in NK cells education. Moreover, as also NK cells
express TLR recognizing viral pattern, an increased TLR-mediated activation of cytokine
production can be envisaged, suggesting a dual role in the NK cell-mediated antiviral
responses. Overall, TRPML channels might play a double-edged sword in resistance to
viral infections: on one side they can promote virus cellular entry and infectivity; on the
other side, by regulating TLR responses in the various immune cells, they contribute to
enhance antiviral innate and possibly adaptive immune responses.
Keywords: TRP channel, mucolipin, innate immunity, viral infection, endolysosome
DISCOVERY AND CHARACTERIZATION OF MUCOLIPIN
CHANNELS
The transient receptor potential mucolipin channels (TRPML) are non-selective cation channels
that conduct Ca2+ and monovalent cation currents from the lumen to the cytoplasm (1, 2).
These channels are tetramers, consisting of proteins with six transmembrane-spanning domains
and amino- and carboxy-terminal tails oriented toward the cytosol (3). Each subunit has six
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SUBCELLULAR LOCALIZATION OF
TRPML CHANNELS
transmembrane segments (S1–S6) and a pore-loop between
S5 and S6, which forms a voltage-sensor-like domain and a
pore domain. A long extracellular linker between S1 and S2,
“polycystin-mucolipin domain” is identified (4). There are three
TRPML subtypes sharing ∼40% amino acid sequence identity
(2). TRPMLs play a role in membrane trafficking (1, 2, 5),
autophagy (6, 7), exocytosis (8), and ion homeostasis (9).
The MCOLN1 gene encoding TRPML1 is located on human
chromosome 19. No splicing variants have been found in
humans, whereas splice variants were described in mice (10).
The MCOLN2 gene encoding TRPML2 is located on human
chromosome 1 and only one TRPML2 isoform showing 60%
amino acid homology with TRPML1, has been detected in
humans. The human MCOLN3 gene maps on the short arm
of chromosome 1.
TRPML1 is expressed in a number of tissues including
adrenal gland, lung, bladder and placenta as well as in thymus,
spleen and immune cells (11–13). Mutations in MCOLN1 gene
cause a lysosomal storage disorder called mucolipidosis type IV
(MLIV). Over 95% of patients with MLIV have loss of functional
mutations in MCOLN1 (11–13). Many patients carry mutations
that introduce premature stop signals in MCOLN1, thus the
TRPML1 protein is completely absent, or abnormally short
and it lacks the ion conducting pore (13–15). Some patients
show single point mutations in MCONL1 that maintain the
open reading frame but lead to a incorrect location or to the
production of a TRPML1 inactive form (11–14, 16–18). TRPML2
mRNA is mainly detected in lymphocytes and other cells of the
immune system (19). In addition, TRPML2 was found to be
overexpressed in aggressive human glioblastoma (20). TRPML3
is mainly expressed in cochlear and vestibular sensory hair
cells and melanocytes (21). Two TRPML3 spontaneous gain-offunction mutations (A419P and I362T) called varitint-waddler
mutations cause deafness and coat color dilution in mice (22–26).
TRPML1 is activated by phosphatidylinositol-3,5-biphosphate
(PtdIns(3, 5)P2) (15, 21, 27–29). Moreover, TRPML1 has
an intraluminal loop whose protonation stimulates channel
activation (24, 30, 31). It is inhibited by phosphatidylinositol4,5-biphosphate (PtdIns(4, 5)P2), sphingomyelins, and lysosomal
adenosine (28, 29). PtdIns(3, 5)P2 is able to activate also
TRPML2 and TRPML3. Na+ removal or less acidic/neutral
pH activate TRPML3 and TRPML2, respectively (32, 33).
Among synthetic activators currently available ML-SA1 activates
TRPML1, TRPML2, and TRPML3 in human; ML2-SA1 is
TRPML2 specific; MK6-83 activates TRPML1 and TRPML3 (15,
21, 28, 32). There are several synthetic inhibitors (ML-SIs);
however, they are unable to discriminate the TRPML isoforms
from each other (7, 8). Therefore, PtdIns(3, 5)P2 seems to have
a central role in activating the TRPML family. This is a lowabundance endolysosome-specific phosphoinositide, produced
by PtdIns (3) P5-kinase (PIKfyve). In the immune response,
PtdIns(3, 5)P2 is responsible for the fusion of phagosomes
with lysosomes to form phagolysosomes, which are essential
for the digestion of engulfed pathogens (11, 12, 21). It should
be noted that the phagosome acidification is allowed because
PtdIns(3, 5)P2 activates TRPML1 channel by directly binding to
its N-terminus (34).
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TRPMLs primarily localize to vesicles along the endocytosis
and exocytosis pathways. TRPML1 is localized in the lysosomeassociated membrane protein (Lamp-1)+ or Rab7+ late
endosomal and lysosomal (LEL) compartment (2, 26, 35, 36).
Late endosomes have an acidic pH of 5.5–6.0, and lysosomes
have a more acidic pH of 4.5–5.0 (37–39), a necessary condition
to maintain the activity of lysosomal hydrolases (40). The
lysosomal localization of TRPML1 protein is likely mediated by
clathrin adaptor AP2-dependent internalization from the plasma
membrane and/or AP1/AP3-dependent trafficking from the
trans-Golgi network (41). Moreover, TRPML1 functions as a key
lysosomal Ca2+ channel controlling both lysosome biogenesis
and reformation, crucial events for cellular homeostasis (42).
TRPML1 also regulates focal exocytosis and phagosome
biogenesis. Phagocytic ingestion of large particles activates
a PtdIns(3, 5)P2- and Ca2+ -dependent exocytosis pathway
necessary for pseudopod extension and for leading to clearance
of senescent and apoptotic cells in vivo (8).
Similar to TRPML1, TRPML2, and TRPML3 co-localize with
Lamp-1 and Rab7 in the LEL compartment (41).
Antigen presentation is central in activating adaptive
immunity and is mainly mediated by professional antigenpresenting cells including dendritic cells (DCs) and macrophages.
In mouse macrophages TRPML1 co-localizes with the MHC-II
molecules (43), and by heteromeric interactions with TRPML2
(44) that also contributes to MHC-II/antigen complex formation.
The TRPML2+ vesicles colocalize with CD63, Lamp-1 and
Lamp-3, and Rab11; they induce accumulation of LysoTracker
(3, 45), indicating that a fraction of TRPML2 is present in LEL.
Numerous proteins, including MHC-I, CD59, interleukin-2
receptor, β1 -integrins, and many glycosylphosphatidylinositolanchored proteins (GPI-APs), travel along the Arf6-regulated
pathway (46–48), and co-localize with TRPML2. In addition,
Arf6 mutations induce sequestration of TRPML2, MHC-I,
and GPI-APs into the same enlarged vacuolar organelles (49),
suggesting that TRPML2 uses the Arf6 pathway to cycle between
the plasma membrane and recycling endosomes. TRPML2
overexpression induces a strong activation of Arf6, while the
inactive form of TRPML2 (D463 D/KK) delays the recycling
of internalized GPI-APs back to the plasma membrane (49).
TRPML2 has been also suggested to participate in the regulation
of the lysosomal compartment of B-lymphocytes (45).
Much less is known about the localization and function of
TRPML3. TRPML3 is localized in the ELs, early endosomal (EEs),
and plasma membrane compartments. Moreover, TRPML3
regulates endocytosis, membrane trafficking and autophagy (50).
GENERAL MECHANISMS FOR VIRUS
ENTRY INTO HOST CELLS
Viruses have developed different mechanisms and molecules to
interact with proteins, lipids and sugar moieties expressed on
the surface of host cells, which generally trigger virion uptake
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TRPML2 doesn’t modulate antiviral signaling in IFN-responsive
A549 cells: indeed, no differences in MX1, interferon induced
transmembrane protein 3, or Interferon alpha inducible protein
27as well as IFNB1 and ISG induction were found in TRPML2expressing cells infected with either IAV or Sindbis virus. Both
IAV and Sindbis virus infections were enhanced by TRPML2.
Accordingly, no IAV infection has been evidenced in TRPML2DD/KK dominant negative mutant stably-transfected A549
cells. Similarly, TRPML3 increased IAV infection in ectopically
expressing cells (65).
Overall, these data suggest that TRPML-mediated increase
of viral infection is not linked to impairment of IFN
or ISG induction.
During virus life cycle, TRPML2 expression increases at
the early, but not at late post-entry stages. No major effects
on adhesion of IAV on A549 cell surface or virus particle
endocytosed cells, have been observed, whereas TRPML2
affected virus vesicular trafficking by promoting the efficiency
of IAV trafficking to late endosomes or by preventing virion
degradation (65), with more IAV fused within the endosomes in
ectopic TRPML2-expressing cells. This effect has been evidenced
only with viruses requiring TRPML2-dependent transport to
endocytic carrier vesicles/late endosomes.
In this regard, a rare genetic variant of human TRPML2,
which induces a lysine/glutamine or arginine change at 370 aa
in TM3 and TM4 domains of TRPML2 protein (MCOLN2K370Q), failed to enhance TRPML2-mediated viral infection
when ectopically expressed. Intriguingly, the frequency of this
variant is rather low (about 3%), but increases (11%) in some
African populations (65).
through the endosomal system (51, 52). Different endocytic cell
routes for virus entry have been reported (53–58). Numerous
host factors are involved in the viral uptake, including coat
proteins (clathrin and caveolin), scission factors (dynamin 2),
and regulatory and trafficking factors (Ras, Ras-related C3
botulinum toxin substrate 1, cell division control protein 42
homolog, and phosphatidylinositol 3-kinase,RabGTPases, etc.)
(59). Endocytosis is a dynamic process and involves recycling,
trafficking, maturation and fusion of endocytic vesicles (60).
Viruses that are running the endocytic gauntlet, need to escape
the endosome before being recycled back into the extracellular
space (61–63), or degradation in the lysosome. Thus, enveloped
viruses (e.g., Filoviridae, Arenaviridae, and Orthomyxoviridae)
fuse the viral envelope with an endosome membrane, releasing
their genomic content into the cytoplasm. Non-enveloped
viruses (e.g., Adenoviridae, Parvoviridae, and Picornaviridae)
use membrane-modifying proteins which can physically pierce
the endosomal membrane to allow release of the genomic
content into the cytoplasm and receptor switching to facilitate
the viral endosomal escape (64). Another feature of viral
endosomal penetration is the ability to co-opt membrane damage
responses of the target cell, by recruiting host phospholipases
(Picornavirus) or inducing lysosomal/autophagosomal exocytosis
(Adenovirus) (65).
Among the receptors involved in virus uptake and antiviral immune responses, a role for TRPMLs in virus infection
as well as in the activation of innate immune responses has
recently been suggested.
TRPMLs ENHANCE VIRUS INFECTIVITY
BY INCREASING THE TRAFFICKING
EFFICIENCY OF ENDOCYTOSED
VIRUSES
TRPML2 CHANNEL TRIGGERS
ANTI-VIRAL INNATE IMMUNE
RESPONSES
Recently, it has been found that TRPML2 channel is one of
the interferon (IFN)-stimulating genes (ISGs). However, as
several ISGs, TRPML2 enhances the infectivity of the yellow
fever virus, the Zika virus, the influenza A virus (IAV) and
the equine arteritis virus, while no effect on the Venezuelan
equine encephalitis virus, respiratory syncytial virus, or
vesicular stomatitis virus has been reported (65–67). Human
A549 lung adenocarcinoma cells, stably transfected with
TRPML2, result in enhanced IAV infectivity and infectious
virus production. Moreover, knockout of TRPML2 in A549
and U-2 OS osteosarcoma cells caused a reduction of viral
infection. In addition, treatment of THP-1 monocytes
with IFN-γ, poly (I:C) or LPS (68, 69) enhanced TRPML2
protein expression.
Specifically, TRPML2 promotes virus trafficking from early
to late endosomes and causes an enhanced viral release into the
cytosol and a consequent escape from endosomal compartments;
thus, it promotes a productive infection. This process requires
TRPML2 channel activity, but doesn’t involve the antiviral IFN
signaling pathways, and broadly is applied to enveloped RNA
viruses that are transported to late endosomes by infection.
Innate immune activation is based on the ability of the host
to recognize pathogens through specific pathogen recognition
receptors such as TLR, NOD-like receptors, lectin-like receptors
and RIG-1 receptors. Engagement of these receptors activates
the production of cytokines, chemokines, and interferons
that by binding to their cognate receptors, signal through the
JAK-STAT pathways and transcriptionally induce hundreds
of ISGs (66, 67). Recent evidence indicates that TRPML2 is
expressed at low levels in resting RAW 264.7 macrophages,
but its expression is strongly induced upon TLR activation,
with no effect on TRPML1 or TRPML3 (68). These data
have been also confirmed in bone marrow and alveolar
macrophages as well as in microglia from mice treated
with a panel of TLR activators, including zymosan (TLR2
ligand), PolyI:C (TLR3 ligand), LPS (TLR4 ligand), R-848
(TLR7/8 ligand), and Imiquimod (TLR7 ligand). Endogenous
TRPML2 co-localizes with perinuclear vesicles that also
contain the transferrin receptor and likely correspond to
recycling endosomes.
It is therefore interesting to consider the implications of
TRPML2 up-regulation during in vivo viral infections, when IFN
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(79), TFEB translocates into the nucleus where it regulates the
TRPML1 expression. Of interest, sensing of bacterial or viral
products also induced the TFEB translocation from the cytosol
to the nucleus with consequent expression of a network of genes
involved in lysosome activity, biogenesis, and secretion (80–83).
Toll like receptors play a crucial role in the early host
detection of invading viruses (84–87). In particular, TLR-7 and
TLR-9 recognize single-stranded RNA (ssRNA) and doublestranded RNA (dsRNA), respectively, in the endolysosomes
(84–86). A recent report demonstrates the involvement of
TRPML1 in TLR7-mediated DC responses by faciliting ssRNA
trafficking into lysosomes. TRPML1−/− DCs showed impaired
TLR7 responses to ssRNA, while a mucolipin agonist specifically
enhanced TLR7 responses to ssRNAs. In addition, the inhibition
of PtdIns(3, 5)P2 generation, that binds directly to TRPML1
and induces the Ca2+ release, completely inhibited TLR7
responses to ssRNA in DCs (88). Confocal analyses showed
that ssRNA transportation to lysosomes in DCs was impaired
by a PIKfyve inhibitor as well as by the lack of TRPML1.
Moreover, in TRPML1−/− bone marrow derived-DCs (BMDCs) RNA transportation to lysosomes was more severely
impaired than DNA transportation. TLR9 responses to CpG-A
were also significantly impaired in TRPML1−/− Bone Marrowconventional DCs (BM-cDCs) and plasmocytoid-DC (pDCs) by
the PIKfyve inhibitor, suggesting that TRPML1 has a role in CpGA transportation to lysosomes. However, CpG-A transportation
to lysosomes was only transiently halted in TRPML1−/− BMcDCs, suggesting a redundant role of TRPML1 in this pathway.
Conversely, TLR9 responses to CpG-B were not altered in
TRPML1−/− BM-cDCs and pDCs (77, 88). Impaired TLR7
and TLR9 responses in TRPML1−/− BM-cDCs stimulated with
ssRNAor CpG-Awas associated with reduced IL-6, TNF-α and
IFN-α production. In addition, the PIKfyve inhibitor induced
an impairment of TLR7 responses to ssRNA in BM-pDCs,
while only reduced production of IFN-α in response to TLR9
stimulation by CpG-A was observed.
A role for TRPML channels in CpG-A transportation is not
limited to TRPML1, but it has been described also for TRPML2
and TRPML3 (88).
Collectively, these findings suggest that TRPML
channels, by enhancing TLR responses and promoting DC
maturation/activation, play a critical role in stimulating antiviral adaptive immune responses. In this regard, it has recently
been discovered that TRPML2 increases the expression of
B7 costimulatory molecules on DC via TFEB activation and
simultaneously induces CD8 T cell proliferation and cytolytic
activity in an antigen-specific manner (89).
is produced and triggers a number of responses. In non-immune
cells, basal or IFN-induced TRPML2 expression may lead to
enhanced viral uptake thus promoting virus infection. However,
in immune cells expressing higher levels of basal TRPML2 (68,
70, 71), TRPML2-mediated increased viral uptake also results in
increased PAMP receptor engagement and activation, stronger
immune response, and subsequently improved viral clearance.
In this regard, apilimod, an inhibitor of PIKfyve by functioning
as activator of the TRPML2 channels, blocks the entry and the
infection of the Ebola virus and the Marburg virus in Huh 7 liver,
in Vero E6 kidney cells and in human primary macrophages.
Apilimod also blocked Ebola-glycoprotein-virus like particle
(VLP) entry and VLP infection (72).
Infection of mouse bone marrow derived macrophages
(BMDM) with the intracellular Mycobacterium smegmatis
induces TRPML2 expression, suggesting that TRPML2 upregulation, occurs not only in response to purified TLR ligands
but also to live pathogens. In addition, TRPML2 knocked-out
mice treated for 24 h with LPS showed reduced expression
of chemokine (C-C motif) ligand (CCL) 3, CCL5, chemokine
(C-X-C motif) ligand 2 and intercellular adhesion molecule 1.
Moreover, the amount of secreted CCL2 a chemokine released
via the early/recycling endosomalwas significantly reduced in the
supernatants from LPS-treated TRPML2−/− BMDM. Similarly,
ML2-SA1 a new TRPML2 agonist, stimulated CCL2 release by
LPS-activated WT but not TRPML2−/− macrophages (73). ML2SA1 treatment also promoted macrophage migration (32), and
macrophage and neutrophil migration, in response to LPS, was
reduced in TRPML2 knocked-out mice (68).
INVOLVEMENT OF TRPML1 IN THE
REGULATION OF TLR RESPONSES IN
DC: POTENTIAL ROLE IN THE
ANTIVIRAL ADAPTIVE IMMUNITY?
Dendritic cells play an important role in the beginning of
specific immune responses. Immature DCs patrol the tissues
and check for the antigen presence by continuously internalizing
extracellular material mainly via micropinocytosis (32, 74).
Sensing of pathogen/danger signals triggers the DC maturation,
reduces the antigen uptake, and up-regulates the membrane
expression of CC-chemokine receptor 7 that binds to CCL21
and CCL19 chemokines, driving DCs to lymph nodes, where
they present the antigen to T cells (75, 76). Recent evidence
indicates that activating the TRPML1-transcription factor EB
(TFEB), by regulating TRPML1 gene expression, allows DCs
to switch from a tissue-patrolling mode to a fast migratory
mode in order to reach the lymph nodes (77). Upon microbial
sensing, lysosomal calcium is released by TRPML1, which in turn
activates myosin II at the cell rear, promoting fast and directional
migration. Lysosomal calcium also induces the activation of
TFEB, that at steady state is phosphorylated by the mammalian
target of rapamycin complex 1 (mTORC1) and remains in
the cytosol (78), but due to the dephoshorylation induced
by the TRPML1-mediated calcium efflux-activated calcineurin
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TRPML1 AND TRPML2 REGULATE OF
NK CELL FUNCTIONS: A DUAL ROLE IN
ANTIVIRAL NK CELL RESPONSES?
Natural killers are a subset of innate lymphoid cells that have
the ability to recognize and eliminate infected cells. Moreover,
they can secrete anti-viral cytokines such as IFN-γ and TNF-α
and chemokines to recruit and instruct other immune cell types
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K562 cells. Overall, these findings suggest an important role of
TRPML1-mediated modulation of secretory lysosomes in NK
cell education (96). Recent evidence reported that NK cells also
express high levels of TRPML2, which further increase during NK
cell differentiation. Silencing of TRPML2 leads to slight enhanced
NK cell degranulation and to the production of IFN-γ (96).
Finally, although no evidence is available in the literature
so far, a role for TRPML in promoting NK cell-mediated TLR
responses to viral patterns can be envisaged (97).
Collectively, these findings suggest that TRPML channels
negatively affecting NK cell education and promoting
TLR activation, play a dual role in NK cell-mediated
antiviral responses.
CONCLUSION
Several evidences indicate that TRPMLs play a crucial role
in membrane trafficking, autophagy, exocytosis and ion
homeostasis. Thanks to these functions, TRPML1 and TRPML2
have been found to be involved in the entry and trafficking of
virus by promoting virus infectivity and productive infection.
Conversely, these receptors are also expressed on innate immune
cells where they stimulate the transport of viral patterns and
therefore the cognition by their respective receptors present in
the endosomal compartment. In DCs, this results in enhanced
TLR responses that lead to increased DC maturation, production
of IFNs, inflammatory cytokines/chemokines and migration
with consequent activation of the anti-viral adaptive immune
responses (Figure 1). Recent findings indicate that on NK cells,
which also express TRPML1 and TRPLM2 as well as the TLRs
recognizing the viral nucleic acids, TRPML1 impairs NK cell
education and functional activity by modulating the secretory
lysosomes, thus suggesting a dual role in the NK cell-mediated
antiviral responses.
For what concern TRPML3 role in infections, it has been
demonstrated in bladder epithelial cells that TRPML3, by
mediating efflux of Ca2+ ions from lysosomes, promotes the
expulsion of exosome-encased bacteria (98). However, little is
known about its functions in viral infections. At this regard,
findings showed that TRPML3 increased IAV infections in
ectopically expressing cells (65). Moreover, it has been recruited
in the autophagosome upon induction of autophagy (50) and this
suggests that it could participate to the xenophagy. Regarding
the viral infections, autophagy can be either pro-viral or antiviral. Some virus exploit the autophagy machinery for their
intracellular survival, while other express specific protein to evade
autophagy and propagate in host cells (99). Thus, an important
role of TRPML3 in viral infections cannot be excluded; however,
additional findings are required to further clarify this issue.
FIGURE 1 | Schematic representation of TRPML1 and TRPML2 involvement
in the regulation of vesicles trafficking induced by pathogen sensing. By
controlling the fluxes of vesicular Ca2+ , TRPML1 promotes in dendritic cells
the activation of myosin II that leads to fast and directional migration whereas
TRPML2 regulates in macrophages the fission/fusion processes of transport
vesicles and so the release of chemokines in the environment. TLR, toll like
receptor; RE, recycling endosome, LY, lysosome; EE, early endosome; rER,
rough endoplasmic reticulum.
(87). The activation of NK cell depends on a delicate balance
between activating and inhibitory signals, the latter mainly being
transduced by (KIRs, CD94/NKG2A) receptors for class I MHC.
The interaction of MHC I inhibitory receptors with their selfligands also results in the acquisition of the effector potential,
a process called NK cell education (90, 91). The recognition of
abnormal self on virus-infected cells triggers a number of nonMHC I-restricted activating receptors such as NKG2D, MHC
I-related molecules MHC class I chain-related protein A and
B (MICA and MICB) and UL16 binding proteins (ULBPs),
DNAX Accessory Molecule-1and the NCR. These activating
receptors function mainly in a cooperative manner to overcome
the inhibitory signals of KIR and CD94-NKG2A receptors (92).
As other innate immune effector cells, NK cells can also sense
viral patterns by means of TLRs. Indeed TLR3, TLR 7, TLR 8, and
TLR 9 have been detected in human NK cells and the engagement
by their respective ligands leads to production IFN-γ and CSFs
and chemokines. Moreover, antiviral NK cell-mediated reactivity
strongly relies on the cross-talk with other innate immune cells,
including DCs and macrophages which can promote NK cell
effector functions and proliferation by secreting cytokines such
as IFN-α/β, IL-12, and IL-15, respectively (93–95).
Recent findings demonstrated that TRPML1 is expressed
at mRNA level in both educated (KIR+ ) and not educated
(KIR− ) NK cell subsets. Interestingly, pharmacological inhibition
of PtdIns(3, 5)P2 synthesis, or genetic silencing of TRPML1,
resulted in enlargement of lysosomal compartment, increased
granzyme B (GZB), and enhanced specific degranulation and
IFN-γ production. On the contrary, stimulation of NK cells
with the TRPML agonist, MK6-83, induced the loss of GZB and
decreased degranulation and IFN-γ production in response to
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AUTHOR CONTRIBUTIONS
GS and AS drafted the manuscript. GS conceived and
designed the study. MM, CA, MN, and MS critically
revised the manuscript.
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FUNDING
ACKNOWLEDGMENTS
This work was supported by MURST 2017 and the Umberto
Veronesi Fondation (Post-doctoral Fellowship 2019 to MM).
We thank Oliviero Marinelli and Federica Maggi for
their assistance.
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Conflict of Interest: The authors declare that the research was conducted in the
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