Activating Transcription Factor 3 and the Nervous System

Hunt, David; Raivich, Gennadij; Anderson, Patrick N.

doi:10.3389/fnmol.2012.00007

Cited by 138 publications

(135 citation statements)

References 186 publications

(243 reference statements)

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“…that likely represents the ATF3b isoform (containing an intact C terminus) (43), which remains to be functionally characterized. Taken together, these data demonstrate that ATF3 induction by type I IFNs is conserved between murine and human immune cells, potentially forming part of an IFN-b negative feedback loop.…”

Section: Type I Ifns Induce Atf3 Expression In Mouse and Human Immunementioning

confidence: 99%

ATF3 Is a Key Regulator of Macrophage IFN Responses

Labzin

Schmidt

Masters

et al. 2015

The Journal of Immunology

103

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Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate immune response to microbial infection. However, the expression of these inflammatory mediators is tightly regulated, as uncontrolled production can result in tissue damage and lead to chronic inflammatory conditions and autoimmune diseases. Activating transcription factor 3 (ATF3) is an important transcriptional modulator that limits the inflammatory response by controlling the expression of a number of cytokines and chemokines. However, its role in modulating IFN responses remains poorly defined. In this study, we demonstrate that ATF3 expression in macrophages is necessary for governing basal IFN-β expression, as well as the magnitude of IFN-β cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-β via direct binding to a previously unidentified specific regulatory site distal to the Ifnb1 promoter. Additionally, we observed that ATF3 itself is a type I IFN–inducible gene, and that ATF3 further modulates the expression of a subset of inflammatory genes downstream of IFN signaling, suggesting it constitutes a key component of an IFN negative feedback loop. Consistent with this, macrophages deficient in Atf3 showed enhanced viral clearance in lymphocytic choriomeningitis virus and vesicular stomatitis virus infection models. Our study therefore demonstrates an important role for ATF3 in modulating IFN responses in macrophages by controlling basal and inducible levels of IFNβ, as well as the expression of genes downstream of IFN signaling.

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Section: Type I Ifns Induce Atf3 Expression In Mouse and Human Immunementioning

confidence: 99%

ATF3 Is a Key Regulator of Macrophage IFN Responses

Labzin

Schmidt

Masters

et al. 2015

The Journal of Immunology

103

View full text Add to dashboard Cite

show abstract

“…ATF3 transcriptional targets vary in different cell types and conditions, resulting in diverse influences on cellular phenomena, such as cell survival, proliferation, and death (15,16). In neurons (17), induction of ATF3 expression prevents cell death and promotes neurite formation and elongation, leading to enhanced nerve regeneration through transcriptional induction of survival and growth-associated genes (18)(19)(20)(21)(22)(23)(24)(25)(26). Intact adult motor neurons do not normally express ATF3.…”

mentioning

confidence: 99%

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

Seijffers

Zhang

Matthews

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance This study reports on the beneficial effects of forcing high expression of the transcription factor activating transcription factor 3 (ATF3) in ALS. ALS is a noncurable adult-onset disease that attacks motor neurons, resulting in paralysis and death. ATF3 overexpression in motor neurons in an ALS mouse model modifies gene expression and drives the neurons into a prosurvival and proregenerative state, increasing motor neuron survival and maintaining axonal connection with muscle by promoting axonal sprouting. ATF3 overexpression results in markedly improved muscle strength and function and delayed disease onset but only slightly increased lifespan. Molecular mechanisms that promote axonal sprouting could substantially improve quality of life in ALS, although additional approaches will be required to overcome progressive motor neuron deterioration.

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“…ATF3 is a member of the ATF/CREB family of transcriptional factors (13,14). The current consensus holds that ATF3 is an immediate early-response gene, a regulator of stress response, and a factor in determining cell fate (15).…”

mentioning

confidence: 99%

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

Shu

Zhou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSVs express a long noncoding RNA, a latency-associated transcript (LAT), which plays a key role in maintaining latently infected neurons, but not viral proteins. To investigate the events leading to reactivation, we examined the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to nerve growth factor (NGF) or delayed reactivation in medium containing NGF and epidermal growth factor (EGF). Here we report the discovery that activating transcription factor 3 (ATF3), a stress response protein, profoundly affects the interaction of HSV with its host. Specifically, (i) ATF3 is induced by stress, such as inhibition of protein synthesis or infection; (ii) in infected cells, ATF3 enhances the accumulation of LAT by acting on the response elements in the promoter of the LAT precursor RNA; (iii) ATF3 is induced nearly 100-fold in ganglionic organ cultures; and (iv) ATF3 plays a key role in the maintenance of the latent state, inasmuch as expression of ATF3 bereft of the C-terminal activation domain acts as a dominant negative factor, inducing HSV gene expression in ganglionic organ cultures harboring latent virus and incubated in medium containing NGF and EGF. Thus, ATF3 is a component of a cluster of cellular proteins that together with LAT maintain the integrity of the neurons harboring latent virus.

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Activating Transcription Factor 3 and the Nervous System

Cited by 138 publications

References 186 publications

ATF3 Is a Key Regulator of Macrophage IFN Responses

ATF3 Is a Key Regulator of Macrophage IFN Responses

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

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