Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)

Knights, Alexander J.; Yik, Jinfen J.; Jusoh, Hanapi Mat; Norton, Laura J.; Funnell, Alister P. W.; Pearson, Richard; Bell-Anderson, Kim; Crossley, Merlin; Quinlan, Kate

doi:10.1074/jbc.m116.715748

Cited by 21 publications

(21 citation statements)

References 50 publications

(79 reference statements)

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“…Interestingly, we have found the 9aaTAD activation domain in Crassostrea gigas, KLF1 ortholog (9aaTAD sequence ELL DYD FIL, gene ID; EKC39171), which closely resembles the first identified 9aaTAD in activator Oaf1 (9aaTAD sequence DLF DYD FLF) (12). Surprisingly, the 9aaTAD activation domains of KLF3 and KLF8 did not activate transcription, which correlated with their repressor function reported previously (52,(81)(82)(83)(84). The accumulation of valines has been shown here again to be associated with the 9aaTAD deactivation (Figures 7).…”

Section: Klf Homology With the Sp Family Revealed Their Activation Dosupporting

confidence: 81%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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The Sp1 transcription factor has been defined as glutamine-rich activator. The Nine amino acid TransActivation Domains (9aaTAD) have been identified in numerous transcription activators. Here, we identified the conserved 9aaTAD motif in the Sp1 and in all nine members of SP family with broad natural 9aaTAD variations. We showed by the amino acid substitutions that the glutamine residues are completely dispensable for 9aaTADs function. We described the 9aaTAD domains' origin and evolutionary history. The ancestral Sp2 gene with inactive 9aaTAD has duplicated in early chordates and created new paralogs Sp1, Sp3 and Sp4. We discovered that the accumulation of valines in the 9aaTADs correlated with the domain inactivation. The Sp2 activation domain, whose dormancy have lasted over 100 million years during chordate evolution, enabled later diversification in the Sp1-4 clade, including both repressors and activators. The new paralogs Sp1 and Sp3 activation domains have regained their original activator function by loss of valines in their 9aaTADs.Keywords: activation domain, 9aaTAD, SP, Sp1, KLF, WT1, Gal4, Met4, Gcn4 and p53. demonstrated the importance of the hydrophobic amino acids for Gcn4 (30-33) and p53 activators (8,(34)(35)(36)(37)(38)(39)(40). Similarly, in the original report for the glutamine-rich activator Sp1(41), the importance of hydrophobic amino acids was already recognized, regardless of the overrepresented glutamines.Nevertheless, the designation as acidic or glutamine-rich activation domains persists to date (42-49).In the human genome, there are about 1,691 annotated transcription factors, divided into 68 groups according to their conserved DNA binding domain (50). The C2H2-type zinc finger is the largest group (682 members), which includes the evolutionally conserved family of KLF activators (Krüppel-like factors). The SP activators (Specificity proteins Sp1-9) belong to a new evolutional branch derived from the ancestral KLF family. The SP activators have been linked to cell proliferation, embryonic development, tissue differentiation, Wnt signaling pathway, metabolism, and their dysregulation has been implicated in a number of human diseases and cancers (51)(52)(53)(54)(55)(56). This report has focused on the SP family and followed the 9aaTAD domain's evolution. MATERIALS AND METHODSConstructs. The construct pBTM116-HA was generated by an insertion of the HA cassette into the EcoRI site of the vector pBTM116. The constructs G1-G45 and H1-H45 were generated by PCR and sub-cloned into pBTM116 EcoRI and BamHI sites. All constructs have a spacer of three amino acids inserted into the EcoRI site; peptide GSG. All constructs have been sequenced by Eurofins Genomics.Further detailed information about constructs and primer sequences are available on request.Assessment of enzyme activities. The β-galactosidase activity was determined in the yeast strain L40 (57,58). The strain L40 has a chromosomally integrated lacZ reporter driven by the lexA operator. In all hybrid assays, we used 2μ vector pBTM116 for...

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Section: Klf Homology With the Sp Family Revealed Their Activation Dosupporting

confidence: 81%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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“…KLF3 has the potential to play numerous roles in a resident population. KLF3 −/− mice show significantly increased production of galectin-3, a mediator of diverse actions including chemotaxis and inflammation (66). Thus, the downregulation of KLF3 further supports brain CD103 + T cells being non-circulating or a highly pro-inflammatory population.…”

Section: Discussionmentioning

confidence: 99%

CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile

et al. 2017

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During chronic infection, memory T cells acquire a unique phenotype and become dependent on different survival signals than those needed for memory T cells generated during an acute infection. The distinction between the role of effector and memory T cells in an environment of persistent antigen remains unclear. Here, in the context of chronic Toxoplasma gondii infection, we demonstrate that a population of CD8 T cells exhibiting a tissue-resident memory (TRM) phenotype accumulates within the brain. We show that this population is distributed throughout the brain in both parenchymal and extraparenchymal spaces. Furthermore, this population is transcriptionally distinct and exhibits a transcriptional signature consistent with the TRM observed in acute viral infections. Finally, we establish that the CD103+ TRM population has an intrinsic capacity to produce both IFN-γ and TNF-α, cytokines critical for parasite control within the central nervous system (CNS). The contribution of this population to pro-inflammatory cytokine production suggests an important role for TRM in protective and ongoing immune responses in the infected CNS.Accession number: GSE95105

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“…Cell culture and transfection. Bone marrowderived macrophages were harvested from femora and tibiae as previously described (24). Equal numbers of WT and Klf3 -/-BMDMs were seeded for all experiments.…”

Section: Methodsmentioning

confidence: 99%

“…KLF3 has been well-established as a key transcription factor in red blood cell development (21)(22)(23), however, the Klf3 -/mouse lacks a severe erythropoietic phenotype. It has recently been shown that KLF3 regulates expression of the inflammatory modulator galectin-3 (24) and is also involved in B cell maturation (25), suggesting a possible link between KLF3, immune cell function and inflammation.…”

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confidence: 99%

“…Here we report that the well-characterized transcriptional repressor KLF3 (21)(22)(23)(24)(26)(27)(28)(29) suppresses NF-κB-mediated inflammation through direct regulation of the p65-encoding gene Rela/RELA. In the absence of KLF3, mice exhibit pronounced systemic inflammation with elevated circulating inflammatory monocytes, constitutive pro-inflammatory cytokine production and a heightened response to endotoxin treatment.…”

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confidence: 99%

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Krüppel-like factor 3 (KLF3) suppresses NF-κB–driven inflammation in mice

Knights

Yang

Shah

et al. 2020

Journal of Biological Chemistry

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Bacterial products such as lipopolysaccharides (or endotoxin) cause systemic inflammation, resulting in a substantial global health burden. The onset, progression, and resolution of the inflammatory response to endotoxin are usually tightly controlled to avoid chronic inflammation. Members of the NF-κB family of transcription factors are key drivers of inflammation that activate sets of genes in response to inflammatory signals. Such responses are typically short-lived and can be suppressed by proteins that act post-translationally, such as the SOCS (suppressor of cytokine signaling) family. Less is known about direct transcriptional regulation of these responses, however. Here, using a combination of in vitro approaches and in vivo animal models, we show that endotoxin treatment induced expression of the well-characterized transcriptional repressor Krüppel-like factor 3 (KLF3), which, in turn, directly repressed the expression of the NF-κB family member RELA/p65. We also observed that KLF3-deficient mice were hypersensitive to endotoxin and exhibited elevated levels of circulating Ly6C+ monocytes and macrophage-derived inflammatory cytokines. These findings reveal that KLF3 is a fundamental suppressor that operates as a feedback inhibitor of RELA/p65 and may be important in facilitating the resolution of inflammation.

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Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)

Cited by 21 publications

References 50 publications

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile

Krüppel-like factor 3 (KLF3) suppresses NF-κB–driven inflammation in mice

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