Proteins related to ZEB1 involved in immune, inflammatory, and membrane/liposomal changes

Protein [59–61]Features and functionsImmune responseInflammationMembrane/Lipids
1. E-cadherin
(Cadherin-1, epithelial cadherin)
Gene
CDH1 (CDHE, UVO)
Localization
Cell junction, cell membrane, endosome, Golgi apparatus		Transmembrane calcium-dependent cell adhesion glycoprotein that constitutes the adherens junctions. Interacts with cytoplasmic actin through alpha, beta, and gamma catenin [62, 63].
CDH1 mutation is associated with cancer [64].
Controls adhesion and locomotion in tumors [63].		Contributes to the maintaining of epithelial barriers which protect the internal tissues.
May take part in modulating transepithelial transfer of immune cells.
Participates in regulating immune cells in the tumor microenvironment, like dendritic cells (DCs) and macrophages [65].		Its overexpression suppresses inflammation by influencing inflammatory signaling pathways [66].The composition of membrane lipids maintains adherens junctions by affecting junctional proteins such as E-cadherin [67].
2. IL-6
(Interleukin-6)
Gene
IL6 (BSF2, CDF, HGF, HSF, IFNB2, IL-6)
Localization
Secreted		Cytokine binds to the IL-6 receptor (IL-6R) and this complex associates with gp130, inducing its dimerization to initiate signaling [68, 69].
Has a pleiotropic effect on inflammation, immune response, and hematopoiesis. Can induce angiogenesis [70].		Promotes differentiation of activated B cells into Ig-producing cells.
Is indispensable for T helper 17 cells differentiation and inhibits regulatory T cells differentiation.
Can promote T follicular helper cells differentiation and production of IL-21 to regulate Ig synthesis [70].		Presents pro- and anti-inflammatory activities [69].
Induces synthesis of acute phase proteins. Activates vascular endothelial cells and induces vascular permeability [70].		-
3. NF-κB
(Nuclear factor-κB: RELA/p65, RELB, NFKB1/p50, REL and NFKB2/p52)
Gene
RELA, RELB, NFKB1, REL and NFKB2
Localization
Nucleus, cytoplasm		Family of transcription factors that regulate innate and adaptive immunity, inflammation, cellular proliferation, differentiation, and survival [71].
In cancer, it may have a dual role, depending on the context, it can promote or repress tumor progression [30, 72].
It stimulates EMT through the upregulation of inducers like ZEB1 [34].		Activated in several immune cells that constitute the tumor microenvironment, promoting or repressing tumor development, such as TAMs, MDSCs, DCs, NK cells, and T and B lymphocytes [72].Plays an important role in coordinating the entire inflammatory response.
Establishes a network with cytokines, like tumor necrosis factor (TNF), IL-1, IL-6, and IL-17A, as well as induces many chemokines, which can promote tumorigenesis and metastasis [72].		-
4. ATGL
(Patatin-like phospholipase domain-containing protein 2, adipose triglyceride lipase)
Gene
PNPLA2 (ATGL)
Localization
Lipid droplet, cell membrane, cytoplasm		Enzyme that catalyzes the first reaction of lipolysis, hydrolyzing triacylglycerols to diacylglycerols, in lipid droplets of adipocytes and non-adipocytes [73].
Its expression is reduced in different cancers [74].		Involved in the production of fatty acids by sPLA2, that intervene in signaling pathways of metabolism, inflammation, immunity, and cancer [73].Provides an important source of fatty acids such as energy substrates, signaling and precursors of membrane lipids [73].
5. PPARα
(Peroxisome proliferator-activated receptor alpha)
Gene
PPARA (NR1C1)
Localization
Nucleus, cytoplasm		Transcription factor regulated by free fatty acids and a key regulator of lipid metabolism [75, 76].
Linked to cancer progression [75].		Participates in the development, differentiation, and functions of immune cells, such as macrophages and T cells [77].One of the key proteins involved in inflammation processes [76].A key regulator for the expression and metabolism of lipids [78].
6. PGC-1α
(Peroxisome proliferator-activated receptor gamma coactivator 1-alpha)
Gene
PPARGC1A (PGC1A)
Localization
Nucleus		Transcriptional coactivator of steroids and nuclear receptors [76].
It has an important role in cancer metabolism. Presents pro- and anti-neoplastic functions [79].		In CD8+ T cells, it promotes cell activation, memory cells, and antitumor immunity [80, 81].
In NK cells, it is important for the effector functions in the response to infection and the control of tumor growth [82].		Low levels in inflamed tissues increase ROS production and oxidative damage [83].It can bind to PPARα, PPARβ/δ, and PPARγ, contributing to the transport and utilization of fatty acids [84].
7. GM3 synthase
(Lactosylceramide alpha 2,3-sialyltransferase)
Gene
ST3GAL5 (SIAT9)
Localization
Golgi apparatus membrane		Enzyme involved in the synthesis of gangliosides, like GM3 [85].
GM3 regulates cell adhesion, growth, and motility through alteration of membrane microdomains and the activation of signaling molecules involved in cancer [86].		Upregulated in CD4+ T cells, in which induces the expression of a-series gangliosides, and downregulated in CD8+ T cells, which express o-series gangliosides.
a-series gangliosides are necessary for CD4+ T cells activation, and o-series gangliosides are required for CD8+ T cells activation [87].		Its participation in inflammation has been studied in pathologies such as renal fibrosis. Its involvement in neoplasia elucidates that it may have an important role in cancer inflammation [88, 89].Participates in the organization of glycolipid microdomains of the membrane during cancer [86, 90].
8. AMPK
(AMP-activated protein kinase)
Gene
PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, PRKAG2, and PRKAG3
Localization
Cytoplasm, nucleus		Protein present in the regulation of cellular energy metabolism [91].
It can act as a tumor suppressor by regulating energy levels in cancer [92].		May regulate activities and functions of immune cells, like macrophages, T cells, B cells, and NK cells, in the tumor microenvironment [93].Participates in inflammation signaling by inhibiting IL-1β expression and NF-κB activation [92].Participates in lipidic remodeling pathways through ferroptosis [94].
9. LXRα
(Liver X receptor alpha)
Gene
NR1H3 (LXRA)
Localization
Nucleus, cytoplasm		Belongs to the nuclear liver X receptors, which respond to changes in levels of lipid ligands and regulate the transcription of genes involved in lipid metabolism [95].In cancer, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1 [96].Necessary for the synthesis of cholesterol in response to inflammatory signals.
Inhibit proinflammatory genes [95, 97].		Regulate the expression of genes encoding proteins involved in the absorption, transport, efflux, excretion, and conversion of cholesterol into bile acids.
Regulate the metabolism of fatty acids and phospholipids [95].
10. ABCA1
(Phospholipid-transporting ATPase ABCA1)
Gene
ABCA1 (ABC1, CERP)
Localization
Cell membrane, endosome		Membrane protein responsible for phospholipids and cholesterol efflux from the cytoplasm [98, 99].
Indirectly represses proliferation, invasion, and metastasis of cancer cells by downregulating the level of intracellular cholesterol [100].		Participates in the activation of anti-tumor Vγ9Vδ2 T lymphocytes, by phosphoantigens, like isopentenyl pyrophosphate (IPP) [101–103].Its deficiency is associated with proinflammatory status, with increases in TNF-α, CCL2, and IL-6 levels [104].Mediates the transfer of phospholipids and cholesterol into apolipoprotein A-I (apoA-I) to generate nascent high-density lipoprotein (nHDL) particles [98, 99].

MDSCs: myeloid-derived suppressor cells; NK: natural killer; ROS: reactive oxygen species; sPLA2: secreted phospholipase A2; TAMs: tumor-associated macrophages