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The Hippo Pathway in Innate Anti-microbial Immunity and Anti-tumor

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DOI: 10.3389/fimmu.2020.01473

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 REVIEW
published: xx July 2020
doi: 10.3389/fimmu.2020.01473
1 58
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6 63

The Hippo Pathway in Innate

7 64
8 65

Anti-microbial Immunity and

9 66
10 67

Anti-tumor Immunity
11 68
12 69
13 70
1,2 1 1,2
14 Qian Zhang , Ruyuan Zhou and Pinglong Xu * 71 Q2 Q3
15 72
1
MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Q4
16 73
Institute, Zhejiang University, Hangzhou, China, 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, Department of
17 74
Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
18 75
19 76
20 The Hippo pathway responds to diverse environmental cues and plays key roles in 77
21 cell fate determination, tissue homeostasis, and organ regeneration. Aberrant Hippo 78
22 79
signaling, on the other hand, has frequently been implicated in diversified pathologies
23 80
24
such as cancer and immune dysfunction. Here, we summarize the recent but rapid 81
25 progress in understanding the involvement of the Hippo pathway in innate immunity, 82
26 with a special focus on the intrinsic mechanisms and mutual interactions between 83
27
Hippo-YAP signaling and the innate immune response and its physiological impacts 84
28 85
on anti-microbial immunity and anti-tumor immunity. Moving forward, we believe that
29 86
30
systematic investigations under the physiological setting are needed to draw a clearer 87
31 picture of the actions of Hippo in innate immunity. 88
32 Edited by: 89
Lanfen Chen, Keywords: Hippo-YAP signaling, innate immunity, anti-tumor, anti-microbial, nucleic acid sensing, pattern Q11
33 90
Xiamen University, China recognition receptor, antiviral immunity, interferon, YAP/TAZ, cGAS-STING
34 91
35 Reviewed by: 92
Kang Wei,
36
The Chinese University of
INTRODUCTION 93
Q12
37 94
Hong Kong, China
38 The Hippo pathway responds to diverse extracellular cues and plays key roles in tissue homeostasis, 95 Q8
Hyun Woo Park,
39 organ regeneration, and tumorigenesis. Originally discovered in Drosophila, the Hippo pathway 96 Q1
Yonsei University, South Korea
40
*Correspondence:
is highly conserved in evolution (1–4). A kinase cascade by four tumor suppressors constitutes 97
41 Pinglong Xu the core of the Hippo pathway, comprising two signaling complexes—the Hpo-Sav (MST-SAV in 98
Q5 42 xupl@zju.edu.cn mammals) and the Wts-Mat (LATS-MOB in mammals), which govern the cellular localization, 99
43 activity, and fate of signaling effectors YAP and TAZ (1, 5–8). Transcription coactivators YAP 100
44 Specialty section: and TAZ therefore serve as downstream effectors in response to unfavorable growth conditions 101
45 This article was submitted to such as those derived from mechanical signals, cell adhesion, GPCR ligands, and cellular stresses 102
46 Molecular Innate Immunity, and instructed by upstream kinases including MST, MAP4Ks, TAO, and AMPK (9–19). Activated 103
a section of the journal
47 LATS1/2 kinases directly phosphorylate five conserved serine residues on YAP (20), which drives 104
Frontiers in Immunology
48 the binding of YAP to 14-3-3 proteins for sequestration and cytoplasmic retention (21, 22) as 105
49 Received: 10 January 2020 well as the ubiquitination and proteasomal degradation (20, 23, 24). Otherwise, YAP/TAZ are 106
Accepted: 05 June 2020
50 localized in the nucleus to form transcription complex and activate the TEAD family transcription 107
Published: xx July 2020
51 factors (25, 26), thereby transcribing target genes to promote cell proliferation, survival, and 108
52 Citation: migration (27). 109
Zhang Q, Zhou R and Xu P (2020) The
53 In drosophila, mutations in major kinases of the Hippo pathway (Hpo/Wts) or their upstream 110
Hippo Pathway in Innate
54
Anti-microbial Immunity and
regulators (Ex, Mer, Kibra, Ft, etc.) lead to overgrowth of eyes, wings, and other organs, mainly due 111
55
Anti-tumor Immunity. to a sustained Yki activation that induces excessive cell proliferation (23, 28). Correspondingly, a 112
56 Front. Immunol. 11:1473. sustained activation of YAP in mouse livers leads to cell transformation and tumor formation (22), 113
57 doi: 10.3389/fimmu.2020.01473 while knocking out of YAP in mouse tissues results in various abnormalities in heart, skin, and 114

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 Zhang et al. Hippo-YAP Signaling in Innate Immunity

115 kidney (29–32). YAP and TAZ are also highly active in stem Activated YAP/TAZ in tumor cells and hepatocyte appears 172
116 cells and ancestral cells of various tissues and play important to be an effective attractant to drive the tissue infiltration of 173
117 roles in the maintenance of stemness (33). TAZ is also involved macrophages in the contexts of the tumor immune-environment 174
118 in maintaining the self-renewal of breast cancer stem cells (34), and organ fibrosis, although the expression levels of YAP/TAZ 175
119 while YAP causes genomic instability in medulloblastoma (35). in macrophages are still a controversial topic (62). For example, 176
120 Taken together, these observations indicate that the activities of the activation of YAP in hepatocellular carcinoma underlies 177
121 YAP/TAZ resulting from Hippo signaling are key factors in cell the M2 macrophage recruitment by tumor-initiating cells 178
122 fate determination and tissue homeostasis. (TICs) (63) or promotes the migration and infiltration of 179
123 M1-like macrophages (53), while the genetic deletion of Mst1/2 180
124 in hepatocytes upregulates MCP1 expression and causes a 181
SIGNALING REGULATION AND
125 massive infiltration of macrophages with mixed M1 and M2 182
126
CROSSTALKS OF THE HIPPO PATHWAY phenotypes, which promotes the development of HCC (64). A 183
127 recent report also showed that YAP in macrophages impaired 184
Since its discovery, the physiological and pathological aspects of
128 the IL-4/IL-13-induced M2 macrophage polarization but 185
the Hippo pathway have been steadily established, particularly in
129 meanwhile promoted the LPS/ IFN-γ-triggered activation of 186
development, homeostasis, and regeneration of organs, including
130 M1 macrophage, which produced excessive IL-6 to aggravate 187
liver, heart, intestine, brain and central nervous system (CNS),
131 intestinal bowel disease (IBD) (65). In another report, CYR61, 188
lung, and kidney (36), and in diseases of cancer, immune
132 but not CCL2/CSF1 (63), functioned as the downstream 189
disorder, and cardiovascular dysfunction (27). The regulation of
133 factor of YAP/TAZ in hepatocytes to attract liver macrophage 190
Hippo-YAP signaling appears to be very complicated (Figure 1),
134 infiltration, leading to liver inflammation and fibrosis (66). 191
and there are crosstalks with the Notch pathway (37), the TGF-
135 These intriguing observations may reflect context- and cellular 192
β pathway (38), the WNT pathway (39), G protein-coupled
136 type-dependency of the Hippo pathway in the regulation of 193
receptor (GPCR) signaling (11, 40), and innate immune signaling
137 macrophage polarization and tissue infiltration. 194
(41, 42). Recently, two studies have revealed that the MAP4K
138 On the other hand, less is known about the role of the Hippo 195
kinase family, including MAP4K1/2/3/5 and MAP4K4/6/7,
139 pathway in DCs, another major group of antigen-presenting 196
directly phosphorylate and activate LATS1/2 independent of
140 cells (APCs) that present antigens to CD8+ T cells and activate 197
MST1/2 (13, 14), indicating the existence of other kinases
141 cytotoxic T cells to obliterate virus, bacteria, and tumor cells 198
involved in LATS1/2 regulation under the distinct tissue and
142 (67–69). Recently, the Chi group found that the DC-specific 199
signaling niches. Moreover, YAP and TAZ are targeted by
143 deletion of MST1/2, but not LATS kinases or YAP/TAZ, leads 200
many other kinases such as AMPK (17, 18), CDK1 (20),
144 to selective disruption of the homeostasis and function of 201
JNK (43), HIPK (44), and the tyrosine kinases c-Abl (45)
145 CD8α+ T cells (51). They revealed that CD8α+ DCs exhibited 202
and the Src family (46–49), indicating that YAP and TAZ
146 a particularly robust oxidative metabolism that critically relies on 203
possess a variety of additional regulations independent of the
147 MST1/2 signaling to maintain both the bioenergetic activities and 204
Hippo pathway. One of the major research focuses regarding
148 mitochondrial dynamics. As a result, MST1/2-deficient CD8α+ 205
the Hippo pathway is on understanding how it integrates
149 DCs were impeded in the presentation of extracellular proteins 206
with cellular intrinsic factors and cooperates with the other
150 and cognate peptides to prime CD8+ T cells (51). This report 207
signaling pathways to regulate a myriad of physiological and
151 unveils the intriguing interaction between immune signaling and 208
pathological processes. In this review, we are focusing our
152 metabolic reprogramming that underlies the unique function of a 209
discussions of the Hippo-YAP pathway on a specific topic,
153 subset of DCs. In addition, Torres-Bacete and colleagues revealed 210
innate immunity.
154 that depending on CCR7-RhoA signaling, MST1 selectively 211
155 regulated the cyto-architecture, endocytosis, and migratory speed 212
156 THE FUNCTION OF THE HIPPO PATHWAY of mature dendritic cells (mDCs) (55). Taken together, these 213
157 IN INNATE IMMUNE CELLS studies suggest that the Hippo pathway may participate in the 214
158 homeostasis and function of DCs via distinct mechanisms. The 215
159 By regulating the transactivation of TEAD family transcription functions of the Hippo pathway in innate immune cells are 216
160 factors, Hippo-YAP signaling exerts critical roles in cell usually independent of LATS kinases and YAP/TAZ effectors, 217
161 proliferation, apoptosis, migration, and pluripotency (50). due to the general deficiency of YAP and TAZ expression in 218
162 Recently, accumulating evidence has suggested that the these cells. 219
163 Hippo pathway is considerably involved in regulation of the 220
164 differentiation, metabolism, and functions of innate immune 221
165 cells (51–56). Macrophages and dendritic cells (DCs) are pivotal THE HIPPO PATHWAY IN REGULATION OF 222
166 types of innate immune cells to connecting the innate and INNATE IMMUNE SIGNALING 223
167 adaptive immunity (57–59). Under physiological conditions, 224
168 macrophages are polarized into M1 type, which mainly Innate immunity, which presents in both immune cells and 225
169 engages in pro-inflammatory and anti-tumor responses, or are non-immune cells, functions as the first defense line of defense 226
170 differentiated into the M2 type, which is mainly responsible against pathogen invasion. The host recognizes the pathogen- 227
171 for anti-inflammatory and pro-tumorigenic signals (60, 61). associated molecular patterns (PAMPs) of pathogens, and this 228

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Q6 FIGURE 1 | The signaling mechanism and regulation of the Hippo pathway in drosophila and mammals. The Hippo pathway answers to a variety of intracellular and
Q7 264 extracellular cues and regulates cell proliferation, survival, and migration via the signaling cascade of MST1/2-LATS1/2-YAP/TAZ-TEADs. 321
265 322
266 323
267 324
triggers immune responses via numerous pattern recognition acid-sensing signaling (33); Deng et al. revealed that YAP/TAZ
268 325
receptors (PRRs) (70), including membrane-anchored Toll-like attenuated NF-κB signaling by directly inhibiting IKKα/β
269 326
receptors (TLRs) and C-type lectin receptors (CLRs) (71, 72), activation in an osteoarthritis murine model (88); Ni et al.
270 327
which are distributed mainly in immune cells, and cytosolic found that YAP was highly expressed in Treg cells to amplify
271 328
receptors such as RIG-I-like receptors (RLRs) (73–76), Cyclic TGFβ-SMAD activation, which strengthened Foxp3 expression
272 329
GMP-AMP synthase (cGAS) (77–80), NOD-like receptors (81, and Treg functions (87). These observations are supported
273 330
82), and AIM2-like receptors (83, 84), which have widespread by the greater severity of inflammatory phenotypes and the
274 331
expression. The Hippo pathway appears considerably involved elevated anti-tumor immunity in mice with YAP and/or TAZ
275 332
in the regulation of innate immunity during pathogen infection, deficiency (87–92). Studies from several independent groups
276 333
which is largely distinct from its canonical roles in organ growth also suggested that YAP activation facilitated the expression of
277 334
control and tissue homeostasis maintenance. Our group and SOCS3 and the suppressed the JAK-STAT inflammatory cascade
278 335
others have revealed that YAP and TAZ functioned as potent in astrocytes (89), and during vascular inflammation, prevented
279 336
suppressors to compromise the production and signaling of NF-κB signaling by associating with TRAF6 and facilitating its
280 337
type I interferons (IFN-Is) (41, 85, 86) and the activation of degradation (90). In the case of myocardial fibrosis, YAP in
281 338
NF-κB (42) and that they served as positive regulators for epicardium promoted the recruitment of suppressive immune
282 339
differentiation of the Treg lymphocytes (87). For example, cells Tregs and thus suppressed the post-infarct inflammatory
283 340
Zhang et al. revealed that YAP and TAZ acted as potent response and myocardial fibrosis (91). These observations under
284 341
suppressors of TBK1, the central kinase in innate nucleic various physiological or pathological conditions thus suggest
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371 FIGURE 2 | The Hippo pathway in innate anti-bacterial immunity. Hippo-YAP signaling is considerably involved in innate anti-bacterial immunity at multiple layers to 428
372 address the activity of TLRs and NF-κB and ROS production. 429
373 430
374 431
375 that YAP and TAZ function as suppressors of innate immune which suppressed NF-κB signaling and thereby decreased the 432
376 signaling and inflammatory responses. production of anti-microbial peptides, eventually compromising 433
377 On the other hand, the Guan group reported that deletion the resistance of host to gram-positive bacteria (42). Upon 434
378 of kinases LATS1/2, which resulted in YAP/TAZ activation, bacterial infection, the Hippo pathway in Drosophila enterocytes 435
379 induced the secretion of nucleic acid-rich extracellular vesicles was coupled with the TGF-β and Src-MAPK pathways to 436
380 (EVs) to promote IFN-I production, dendritic cell maturation, upregulate the transcription of upd3, which contributed to 437
381 and CD8+ T-cell expansion and eventually contributed to anti- intestinal stem cell-dependent tissue repair (96). In contrast, 438
382 tumor immunity (93). YAP was also shown to promote NF-κB LegK7, the effector kinase of L. pneumophila, could mimic the 439
383 signaling by suppressing USP31, a negative regulator of NF-κB host MST1 kinase to trigger the degradation of YAP/TAZ, which 440
384 signaling, which resulted in the acceleration of sarcomagenesis interfered with PPARγ activity and altered the transcriptional 441
385 (94). In endothelial cells, the activity of YAP/TAZ was suppressed profile to impair macrophage anti-bacterial immunity (97). 442
386 by atheroprotective unidirectional shear stress, which resulted Therefore, the precise mechanisms and physiological roles of 443
387 in downregulated expression of pro-inflammatory genes and Hippo-YAP signaling in innate anti-bacterial immunity may 444
388 decreased monocyte infiltration (95). Therefore, the roles of await further investigation. 445
389 YAP/TAZ in innate immune signaling and inflammation appear On the other hand, several studies have unveiled that 446
390 to be highly context-dependent. other core components of the Hippo pathway, independent of 447
391 the canonical effectors YAP/TAZ, engage in the regulation of 448
392 innate anti-bacterial immunity. For instance, MST1/2 kinases 449
393 THE HIPPO PATHWAY IN INNATE promoted mitochondria trafficking and reactive oxygen species 450
394 ANTI-BACTERIAL IMMUNITY (ROS) production in phagocytes (98), which facilitated anti- 451
395 bacterial responses and bactericidal activity (99). Mechanistically, 452
396 Organisms from drosophila to mammals are widely armed with MST1/2 facilitated the formation of TLR-triggered TRAF6- 453
397 TLR-mediated anti-microbial responses. The Pan group found ECSIT complex, which recruited mitochondria to phagosomes 454
398 that silencing of the Hippo pathway or activation of Yorkie in and accelerated the production of mitochondrial ROS (98). 455
399 drosophila fat bodies led to an increase in cactus expression, Intriguingly, MST1 disrupted the secretion of TLR4/9-triggered 456

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494 FIGURE 3 | The Hippo pathway in innate antiviral immunity. Hippo-YAP signaling connects the extracellular cues to innate antiviral responses via complex regulations 551
495 at multiple levels and in distinct physiological contexts. 552
496 553
497 554
498 inflammatory cytokines to avoid chronic inflammation in essential component of innate antiviral immunity. RIG-I- 555
499 hepatocellular carcinomas (HCCs) via priming the degradation like receptors (RLRs, including RIG-I and MDA5) surveil 556
500 of IRAK1 in macrophages (100). MST4, a homologous kinase for heterogonous or aberrant RNA molecules (73–76), while 557
501 of MST1/2, also restricted inflammatory responses via the abnormal nuclear or mitochondrial DNA molecules are primarily 558
502 phosphorylation of TRAF6 (101). Taken together, these studies sensed by cGAS (77–80), which initiates cGAS-STING signaling, 559
503 suggest an important but complicated role for the Hippo or by Aim2, which initiates the inflammasomal program. 560
504 pathway, canonical or non-canonical, in innate anti-bacterial Facilitated by mitochondrial or endoplasmic reticulum-localized 561
505 immunity (Figure 2). adaptor proteins MAVS/VISA/IPS-1/Cardif (102–104) or 562
506 STING/MITA/ERIS (105, 106), nucleic acid sensing activates 563
507 TBK1 and IKKε, which are responsible for phosphorylation 564
508 and mobilization of IRF3. Activated IRF3 is then dimerized 565
509 THE HIPPO-YAP PATHWAY IN INNATE and translocated into the nucleus where it functions as a 566
510 ANTIVIRAL IMMUNITY transcriptional factor by synergizing with NF-κB to transcribe 567
511 type I IFNs and ISGs, eventually establishing an appropriate 568
512 In vertebrates, cytoplasmic nucleic acid sensing, which monitors immune state and modulating the adaptive immunity (107, 108). 569
513 both foreign and aberrant nucleic acids in the cytosol, is an Our group found that YAP and TAZ functioned as intrinsic 570

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 Zhang et al. Hippo-YAP Signaling in Innate Immunity

571 628
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FIGURE 4 | The emerging roles of Hippo-YAP signaling in the modulation of innate anti-tumor immunity. The Hippo pathway maneuvers anti-tumor immune
609 666
responses and tumorigenesis via regulating the production of type I IFNs and the infiltration, polarization, and maturation of innate immune cells.
610 667
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612 669
613
inhibitors of TBK1, being directly associated with TBK1 and kinases and YAP/TAZ, MST1 directly associated with and 670
614
preventing the K63-linked ubiquitination and activation of phosphorylated IRF3 to attenuate its dimerization and promoter 671
615
TBK1 (41). In contrast, cellular conditions favoring YAP/TAZ binding (109), and our and other groups further revealed that 672
616
inactivation and degradation relieved this YAP/TAZ-mediated MST1 was also suppressive of TBK1 activation (109, 110). 673
617
TBK1 suppression and thus augmented the antiviral immunity During HIV-1 infection, the CLRs DC-SIGN recognized the 674
618
(41). Zhou and colleagues also showed a few months later that abortive HIV-1 RNA and triggered Raf-1-dependent MST1 675
619
YAP in macrophages negatively regulated the antiviral response activation, which facilitated the phosphorylation and activation 676
620
via interfering with IRF3 dimerization and nuclear translocation of mitotic kinase PLK1 to restrain TBK1 and thus compromise 677
621
(85). Other groups also revealed that YAP/TAZ attenuated MAVS antiviral signaling (110). Given the overall deficiency 678
622
NF-κB signaling by directly inhibiting IKKα/β activation in an of YAP/TAZ expression in many types of immune cells, the 679
623
osteoarthritis murine model (88) and by associating with TRAF6 observations with regard to the similarity but not the distinction 680
624
and facilitating TRAF6 degradation in vascular inflammation of YAP/TAZ and MST1 in innate immunity are rather intriguing. 681
625
(90). Recently, the Yu group reported that an isoform of TAZ Taken together, these observations suggest a considerable 682
626
impeded JAK-STAT signaling to dampen the type I IFNs pathway involvement of the Hippo pathway in innate antiviral immunity 683
627
(86). In addition, our group found that, independent of LATS and the negative effects of YAP/TAZ and MST1 in antiviral 684

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 Zhang et al. Hippo-YAP Signaling in Innate Immunity

685 immunity, depending on the distinct physiological contexts regulation. In this review, we have summarized the intriguing but 742
686 (Figure 3). complex integrations of Hippo-YAP signaling in the functioning 743
687 of innate immune cells and signaling with specific focuses on 744
688 the innate anti-microbial immunity and anti-tumor immunity. 745
689
EMERGING ROLES OF HIPPO-YAP An intuitive part of the nature of the Hippo pathway is its 746 Q13
690
SIGNALING IN MODULATION OF INNATE very complicated interactions with innate immune signaling 747
691 ANTI-TUMOR IMMUNITY at multiple levels and independent or dependent of signaling 748
692 effectors YAP/TAZ. The entirely distinct programs for the 749
693 Type I IFNs bridge innate immunity and adaptive immunity and expression of these core signaling players in innate immune cells, 750
694 play a pivotal role in anti-tumor immunity (111–113). Given particularly YAP and TAZ, appear to justify this requirement. 751
695 that there are numerous lines of evidence for the participation In conclusion, Hippo signaling through the kinase cascade 752
696 of the Hippo pathway in innate immunity, it is no surprise to YAP/TAZ is a conceptually straightforward pathway. 753
697 that Hippo-YAP signaling also effects anti-tumor immunity. For However, we have observed the amazing versatility and context- 754
698 example, the Guan group suggested an unexpected function dependence of the Hippo pathway responses in innate immunity. 755
699 of the Hippo pathway in suppression of anti-tumor immunity Moving forward, we believe that systematic investigations under 756
700 in three murine models. Tumor cells with LATS1/2 deficiency physiological settings are particularly needed to decipher the 757
701 secreted nucleic acid-rich EVs to facilitate TLRs-Myd88/TRIF diversified functions and mechanisms of the Hippo pathway, 758
702 signaling and type I IFN production, which accelerated DC which, ultimately, will guide us to maneuver this critical pathway 759
703 maturation, CD8+ T lymphocyte expansion, and tumor growth to benefit our health. 760
704 arrest (93). In contrast, the Zhao group found that in liver 761
tumor-initiating cells (TICs), YAP recruited M2 macrophages to
705 AUTHOR CONTRIBUTIONS 762
706 suppress immune clearance, thus promoting tumorigenesis (63). 763
707 In human HCC, the Yang group also reported that YAP activation QZ and PX reviewed the literature and wrote the manuscript. 764 Q9
708 induced the polarization of M1/M2 macrophages via Mcp1, RZ contributed with data analyses and discussions. All authors 765
709 thus contributing to massive macrophage infiltration and HCC contributed to the article and approved the submitted version. 766
710 progression (64). The Dey group reported that hyperactivated 767
TAZ, but not YAP, accelerated liver inflammation and tumor
711
development in a TEAD-dependent manner to induce myeloid
FUNDING 768
712 769
713 cell infiltration and pro-inflammatory cytokine secretion (114). The research described in the authors’ laboratories was partly 770 Q10
714 These somewhat diverse observations may reflect the fact that the supported by grants of the NSFC Distinguished Young Scholars 771
715 complex tumor microenvironment and cancer cell types precisely Program (31725017 to PX), the NSFC Projects (31830052 to PX 772
716 determine the exact role of the Hippo-YAP signaling pathways in and 81902915 to QZ), and the Initiative Postdocs Supporting 773 Q14
717 innate anti-tumor immunity. Future investigations are warranted Program (BX20180270 to QZ). 774
718 to define these elaborate situations (Figure 4). 775
719
ACKNOWLEDGMENTS 776
720
CONCLUDING REMARKS 777
721 In reviewing recent advances, we had to limit ourselves to 778
722 Contrary to the classic functions of Hippo-YAP signaling in cell only some observations illustrating the roles of Hippo-YAP 779
723 fate determination, tissue homeostasis, and organ development, signaling in innate immunity. Inevitably, many highly relevant 780
724 accumulating data in recent years has clearly pointed to the findings could not be included. We therefore apologize to those 781
725 critical roles of the Hippo-YAP pathway in innate immune researchers whose work was not included in this review. 782
726 783
727 784
728 785
729
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Frontiers in Immunology | www.frontiersin.org 10 July 2020 | Volume 11 | Article 1473

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