At the intersection of DNA damage and immune responses

Bednarski, Jeffrey J.; Sleckman, Barry P.

doi:10.1038/s41577-019-0135-6

Cited by 117 publications

(105 citation statements)

References 107 publications

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“…Accordingly, at the functional level, we observed that the ROS levels were reduced after two subsequent V. splendidus challenges, suggesting that hemocytes could prevent an uncontrolled respiratory burst. Moreover, hemocytes seem to avoid cellular impairment caused by DNA damage resulting from previous oxidative stress (54), with the overexpression after the second injection of the DNA repair protein XPA (55).…”

Section: Discussionmentioning

confidence: 99%

Immune Tolerance in Mytilus galloprovincialis Hemocytes After Repeated Contact With Vibrio splendidus

et al. 2019

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Mediterranean mussels ( Mytilus galloprovincialis ) are sessile filter feeders that live in close contact with numerous marine microorganisms. As is the case in all invertebrates, mussels lack an adaptive immune system, but they respond to pathogens, injuries or environmental stress in a very efficient manner. However, it is not known if they are able to modify their immune response when they reencounter the same pathogen. In this work, we studied the transcriptomic response of mussel hemocytes before and after two consecutive sublethal challenges with Vibrio splendidus . The first exposure significantly regulated genes related to inflammation, migration and response to bacteria. However, after the second exposure, the differentially expressed genes were related to the control and inhibition of ROS production and the resolution of the inflammatory response. Our results also show that the second injection with V. splendidus led to changes at the transcriptional (control of the expression of pro-inflammatory transcripts), cellular (shift in the hemocyte population distribution), and functional levels (inhibition of ROS production). These results suggest that a modified immune response after the second challenge allowed the mussels to tolerate rather than fight the infection, which minimized tissue damage.

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Section: Discussionmentioning

confidence: 99%

Immune Tolerance in Mytilus galloprovincialis Hemocytes After Repeated Contact With Vibrio splendidus

et al. 2019

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“…DNA damage arises more frequently when exposed to genotoxic therapies such as chemotherapies [60]. Among all forms of damage, the double-stranded breaks (DSBs) of DNA strains are the severest type [61]. These damages can be rescued by two basic DNA DSB repair ways: homologous recombination (HR) and nonhomologous end joining (NHEJ) [62][63][64].…”

Section: Cgas and Nuclear Dna Cgas Interacting With Endogenous Dna Inmentioning

confidence: 99%

cGAS/STING: novel perspectives of the classic pathway

Gao

Tang

et al. 2020

Mol Biomed

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Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor and innate immune response initiator. Binding with exogenous or endogenous nucleic acids, cGAS activates its downstream adaptor, stimulator of interferon genes (STING). STING then triggers protective immune to enable the elimination of the pathogens and the clearance of cancerous cells. Apparently, aberrantly activated by self-DNA, cGAS/STING pathway is threatening to cause autoimmune and inflammatory diseases. The effects of cGAS/STING in defenses against infection and autoimmune diseases have been well studied, still it is worthwhile to discuss the roles of cGAS/STING pathway beyond the “classical” realm of innate immunity. Recent studies have revealed its involvement in non-canonical inflammasome formation, calcium hemostasis regulation, endoplasmic reticulum (ER) stress response, perception of leaking mitochondrial DNA (mtDNA), autophagy induction, cellular senescence and senescence-associated secretory phenotype (SASP) production, providing an exciting area for future exploration. Previous studies generally focused on the function of cGAS/STING pathway in cytoplasm and immune response. In this review, we summarize the latest research of this pathway on the regulation of other physiological process and STING independent reactions to DNA in micronuclei and nuclei. Together, these studies provide a new perspective of cGAS/STING pathway in human diseases.

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“…We observed numerous transition mutations on the proviral plus strand, which is not typical of mA3 (23–25). In contrast, an Apobec family member, activation-induced cytidine deaminase (AID), is known to cause hypermutations on both strands of immunoglobulin genes during B-cell differentiation (26, 27). Differences in MMTV proviral load and most proviral mutations were eliminated in AID-deficient ( Aicda −/− ) mice lacking murine AID (mAID) expression.…”

Section: Introductionmentioning

confidence: 99%

A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus

Singh

Byun

Ali

et al. 2019

mBio

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Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest that rem specifies a human-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes. IMPORTANCE Complex retroviruses, such as human-pathogenic immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.

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At the intersection of DNA damage and immune responses

Cited by 117 publications

References 107 publications

Immune Tolerance in Mytilus galloprovincialis Hemocytes After Repeated Contact With Vibrio splendidus

Immune Tolerance in Mytilus galloprovincialis Hemocytes After Repeated Contact With Vibrio splendidus

cGAS/STING: novel perspectives of the classic pathway

A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus

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