Inhaled TRIM72 Protein Protects Ventilation Injury to the Lung through Injury-guided Cell Repair

Nagre, Nagaraja N.; Cong, Xiaofei; Ji, Hong‐Long; Schreiber, John M.; Fu, Hongyun; Pepper, Ian; Warren, Seth; Sill, Joshua; Hubmayr, Rolf D.; Zhao, Xiaoli

doi:10.1165/rcmb.2017-0364oc

Cited by 19 publications

(32 citation statements)

References 69 publications

(129 reference statements)

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“…Such data argue that TRIM14 acts as a negative regulator of cytosolic DNA sensing through bringing TBK1 and STAT3 together to promote phosphorylation of STAT3 at Ser727. Trim14 KO macrophages were remarkably efficient at limiting M. tuberculosis replication but permissive for vesicular stomatitis virus (VSV), consistent with previous reports (26).…”

Section: Introductionsupporting

confidence: 91%

“…A previous study demonstrated a similar role for TRIM14 in controlling VSV replication but reported that TRIM14 KO macrophages had lower ISG expression compared to wild-type (26).…”

Section: Loss Of Trim14 Impacts the Ability Of Macrophages To Controlmentioning

confidence: 78%

“…Based on its recent characterization as a regulator of cGAS stability (26), we decided to investigate a role for TRIM14 during M. tuberculosis infection. RT-qPCR analysis confirmed that…”

Section: Trim14 Is a Player In M Tuberculosis Infection Of Macrophagesmentioning

confidence: 99%

“…In the context of RNA sensing, TRIM14 has been shown to localize to mitochondria and interact with the antiviral signaling adapter MAVS (25). More recently, TRIM14 has been shown to promote cGAS stability by recruiting the deubiquitinase USP14 and preventing autophagosomal targeting of cGAS (26).…”

Section: Introductionmentioning

confidence: 99%

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TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection

Hoffpauir

Bell

West

et al. 2019

Preprint

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Tripartite motif family proteins (TRIMs) are well-characterized regulators of type I interferon (IFN) expression following cytosolic nucleic acid sensing. While many TRIMs are known to regulate innate immunity to viruses, their contribution to innate immune signaling and gene expression during bacterial infection remains largely unknown. Because Mycobacterium tuberculosis is a potent activator of cGAS-dependent cytosolic DNA sensing, we set out to investigate a role for TRIM proteins in regulating macrophage responses to M. tuberculosis. Here, we demonstrate that TRIM14, a non-canonical TRIM that lacks an E3 ligase RING domain, is a critical negative regulator of the type I IFN response in macrophages. We show TRIM14 physically interacts with both cGAS and TBK1 and that macrophages lacking TRIM14 dramatically hyperinduce interferon stimulated gene (ISG) expression following cytosolic nucleic acid agonist transfection, IFN-b treatment, and M. tuberculosis infection. Consistent with loss of negative regulation in these cells, Trim14 knockout (KO) macrophages have more phospho-Ser754 STAT3 relative to phospho-727 and fail to upregulate the STAT3 target Socs3 (Suppressor of Cytokine Signaling 3), which is required to turn off type I IFN signaling. These data support a model whereby TRIM14 acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 at Ser727 and promote negative regulation of ISG expression. Remarkably, Trim14 KO macrophages are significantly better than control cells at limiting M. tuberculosis replication. Collectively, these data reveal a previously unappreciated role for TRIM proteins in regulating type I IFN responses in response to cytosolic DNA sensing and M. tuberculosis infection. 2 fold-change) in TRIM family genes in BMDMS infected with WT vs ΔESX-1 M. tuberculosis. (D) RT-qPCR of fold-change in Trim14 transcripts in BMDMs stimulated with ISD or infected with WT M. tuberculosis. (E) RAW 264.7 cells infected with mCherry M. tuberculosis for 6 hours and immunostained for TRIM14. Statistical significance was determined using two-tailed students' t test.

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Section: Introductionsupporting

confidence: 91%

“…A previous study demonstrated a similar role for TRIM14 in controlling VSV replication but reported that TRIM14 KO macrophages had lower ISG expression compared to wild-type (26).…”

Section: Loss Of Trim14 Impacts the Ability Of Macrophages To Controlmentioning

confidence: 78%

“…Based on its recent characterization as a regulator of cGAS stability (26), we decided to investigate a role for TRIM14 during M. tuberculosis infection. RT-qPCR analysis confirmed that…”

Section: Trim14 Is a Player In M Tuberculosis Infection Of Macrophagesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection

Hoffpauir

Bell

West

et al. 2019

Preprint

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“…Interestingly, rhMG53 has been very successful in treating ischemia/reperfusion injury and has been also used in the treatment of skeletal muscle [25,26], cardiac muscle [27], and liver tissue [22]. Also, aerosolized rhMG53 has ameliorated the effects of ventilator-induced lung injury [7,28]. These studies introduce the possibility that rhMG53 could be used to increase the repair capacity of other non-muscle cell types like neurons.…”

Section: Introductionmentioning

confidence: 99%

Enhancing membrane repair increases regeneration in a sciatic injury model

et al. 2020

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Various injuries to the neural tissues can cause irreversible damage to multiple functions of the nervous system ranging from motor control to cognitive function. The limited treatment options available for patients have led to extensive interest in studying the mechanisms of neuronal regeneration and recovery from injury. Since many neurons are terminally differentiated, by increasing cell survival following injury it may be possible to minimize the impact of these injuries and provide translational potential for treatment of neuronal diseases. While several cell types are known to survive injury through plasma membrane repair mechanisms, there has been little investigation of membrane repair in neurons and even fewer efforts to target membrane repair as a therapy in neurons. Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle-enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in skeletal muscle. Interestingly, recombinant human MG53 (rhMG53) can be applied exogenously to increase membrane repair capacity both in vitro and in vivo. Increasing the membrane repair capacity of neurons could potentially minimize the death of these cells and affect the progression of various neuronal diseases. In this study we assess the therapeutic potential of rhMG53 to increase membrane repair in cultured neurons and in an in vivo mouse model of neurotrauma. We found that a robust repair response exists in various neuronal cells and that rhMG53 can increase neuronal membrane repair both in vitro and in vivo. These findings provide direct evidence of conserved membrane repair responses in neurons and that these repair mechanisms can be targeted as a potential therapeutic approach for neuronal injury.

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Alveolar epithelial cell integrity: A venerable target in the lung

Pepper

Zhao

2019

Current Topics in Membranes

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Inhaled TRIM72 Protein Protects Ventilation Injury to the Lung through Injury-guided Cell Repair

Cited by 19 publications

References 69 publications

TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection

TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection

Enhancing membrane repair increases regeneration in a sciatic injury model

Alveolar epithelial cell integrity: A venerable target in the lung

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