PML and PML-like exonucleases restrict retrotransposons in jawed vertebrates

Mathavarajah, Sabateeshan; Vergunst, Kathleen L.; Habib, Elias; Williams, Shelby K.; He, Raymond; Maliougina, Maria; Park, Mika; Salsman, Jayme; Roy, Stéphane; Braasch, Ingo; Roger, Andrew J.; Langelaan, David N.; Dellaire, Graham

doi:10.1093/nar/gkad152

Cited by 7 publications

(10 citation statements)

References 99 publications

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“…The Plex9.1 enzyme is also capable of suppressing cGAS-STING (Mathavarajah et al, 2023); however, we did not observe significant changes in Plex9.1 expression during gar regeneration. Therefore, we sought to determine if Plex9.1 may be differentially regulated to influence cGAS-STING signaling in another biological process, such as aging.…”

Section: Plex9 Enzymes Have Elevated Expression In the Cardiac Tissue...contrasting

confidence: 91%

“…For example, LINE-1 retroelements were recently shown to promote the SASP through the activation of cGAS-STING (De Cecco et al, 2019). Previously, we have demonstrated that Pml, Trex1, and Plex9.1 collectively suppress LINE retroelements in an exonucleaseindependent manner to limit cGAS activation (Mathavarajah et al, 2023).…”

Section: Discussionmentioning

confidence: 89%

“…In data assoiated with previous work, we identified plex9.1 among the downregulated genes during cardiomyocyte regeneration (Wu et al, 2016), akin to pml during gar caudal fin regeneration (Figure 1). We observe that ray-finned fish plex9.1, which functions akin to tetrapod Trex1 (Mathavarajah et al, 2023) is also downregulated in the hearts of aged zebrafish, which correlates to elevated cGAS activity (Figure 3). This is consistent with Plex9.1 playing a potentially important role in maintaining cardiac function in teleost fish during aging, which is consistent with previous work demonstrating that mice lacking Trex1 exhibit severe inflammatory myocarditis, cardiomyopathy, and eventually circulatory failure (Morita et al, 2004;Stetson et al, 2008).…”

Section: Discussionmentioning

confidence: 92%

“…However, the expression of cGAS and STING orthologs in the gar fin regenerative blastema did not significantly change. We next surveyed two recently identified suppressor proteins of cGAS activity in gar, Plex9.1 and Pml (Mathavarajah et al, 2023). While we observed no changes to plex9.1 expression, there was a ~8‐fold reduction in pml gene expression at 7 dpa.…”

Section: Resultsmentioning

confidence: 99%

“…A key brake on cGAS‐STING is mammalian TREX1, an exonuclease that degrades cytoplasmic DNA and suppresses LINE‐1 to prevent cGAS activation (Ablasser et al, 2014; Mathavarajah et al, 2019; Thomas et al, 2017). Recently, we showed that in aquatic vertebrates, the promyelocytic leukemia (PML) protein and newly discovered DEDDh exonucleases known as the PML‐like exon 9 (Plex9) proteins can suppress the cGAS‐STING pathway through their exonuclease function and through exonuclease‐independent suppression of LINE‐1, akin to mammalian TREX1 (Mathavarajah et al, 2023). Despite the known role of cGAS‐STING in wound healing and tissue regeneration discussed above, it remains unclear the extent to which the exonuclease suppressors of this pathway play a deeply conserved role in tissue regeneration in other vertebrate species, or if thes pathway is an evolutionary innovation of the mammalian lineage.…”

Section: Introductionmentioning

confidence: 99%

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Suppressors of cGAS‐STING are downregulated during fin‐limb regeneration and aging in aquatic vertebrates

Mathavarajah,

Thompson,

Stoyek

et al. 2023

J Exp Zool Pt B

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During the early stages of limb and fin regeneration in aquatic vertebrates (i.e., fishes and amphibians), blastema undergo transcriptional rewiring of innate immune signaling pathways to promote immune cell recruitment. In mammals, a fundamental component of innate immune signaling is the cytosolic DNA sensing pathway, cGAS‐STING. However, to what extent the cGAS‐STING pathway influences regeneration in aquatic anamniotes is unknown. In jawed vertebrates, negative regulation of cGAS‐STING activity is accomplished by suppressors of cytosolic DNA such as Trex1, Pml, and PML‐like exon 9 (Plex9) exonucleases. Here, we examine the expression of these suppressors of cGAS‐STING, as well as inflammatory genes and cGAS activity during caudal fin and limb regeneration using the spotted gar (Lepisosteus oculatus) and axolotl (Ambystoma mexicanum) model species, and during age‐related senescence in zebrafish (Danio rerio). In the regenerative blastema of wounded gar and axolotl, we observe increased inflammatory gene expression, including interferon genes and interleukins 6 and 8. We also observed a decrease in axolotl Trex1 and gar pml expression during the early phases of wound healing which correlates with a dramatic increase in cGAS activity. In contrast, the plex9.1 gene does not change in expression during wound healing in gar. However, we observed decreased expression of plex9.1 in the senescing cardiac tissue of aged zebrafish, where 2′3′‐cGAMP levels are elevated. Finally, we demonstrate a similar pattern of Trex1, pml, and plex9.1 gene regulation across species in response to exogenous 2′3′‐cGAMP. Thus, during the early stages of limb‐fin regeneration, Pml, Trex1, and Plex9.1 exonucleases are downregulated, presumably to allow an evolutionarily ancient cGAS‐STING activity to promote inflammation and the recruitment of immune cells.

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Section: Plex9 Enzymes Have Elevated Expression In the Cardiac Tissue...contrasting

confidence: 91%

Section: Discussionmentioning

confidence: 89%