Search
Search articles by title, abstract,author or doi
Advanced search

Itaconate keeps endogenous retroviruses quiet

Carlos de la Calle Fabregat , Javiera Villar , Florent Ginhoux

Vita ››

PDF (943KB)
Vita > Cutting Edge > DOI: 10.15302/vita.2026.09.0070
Vita Open AccessPublished:

Itaconate keeps endogenous retroviruses quiet

Author information +
History +
Vita () Cite this article
PDF (943KB)

The immuno-metabolite itaconate, which is produced by inflammatory macrophages, is identified as a direct inhibitor of the m6A RNA demethylase ALKBH5. By preserving m6A modification on endogenous retrovirus RNA transcripts, itaconate promotes their degradation and restrains type I interferon signaling, constituting a metabolic safeguard against chronic inflammation1.

登录浏览全文

4963

注册一个新账户 忘记密码

Endogenous retroviruses (ERVs) represent a major fraction of mammalian genomes; however, they are normally kept transcriptionally silent. Immune activation induces chromatin remodeling, which licenses the transcription of previously silenced ERVs. The resulting ERV-derived nucleic acids drive sustained type I interferon production and tissue-damaging inflammation. Upon inflammatory activation, macrophages also mount regulatory responses through extensive transcriptional and metabolic reprogramming. However, the regulation of retroelement expression during this process remains unclear. Here, Huang and colleagues1 uncovered a molecular safeguard of pathogenic inflammation by modulating ERV expression through metabolic regulation. They show that itaconic acid (ITA), produced by the enzyme IRG1 (encoded by ACOD1), directly inhibits the RNA demethylase ALKBH5 activity through competitive displacement of α-ketoglutarate (α-KG). As a result, ERV transcripts preserve the N6-methyladenosine (m6A) modification, which promotes their degradation and prevents the accumulation of immunostimulatory retroviral nucleic acids (Fig. 1). The work identifies an IRG1–ITA–ALKBH5 axis that limits the transition from acute immune activation to chronic inflammation.
Itaconate is a known regulator of macrophage activation. Typically associated with anti-inflammatory effects, its reported actions include inhibiting succinate dehydrogenase (SDH), limiting IL-1β production, activating NRF2 to induce antioxidant responses, restraining aerobic glycolysis, and dampening TLR-driven secondary responses2. Importantly, ITA acts as a structural analogue of α-KG and has been shown to compete for the active site of α-KG-dependent enzymes, the TET DNA dioxygenases being the best-characterized example3. This finding previously identified ITA as a metabolic-epigenetic mediator, restraining TET2-dependent reprogramming associated with the macrophage pro-inflammatory program.
The present study extends ITA's functional repertoire to the regulation of endogenous retroviruses. The authors found that, following inflammatory stimulation, murine bone marrow-derived macrophages accumulated transcripts from several ERV families, notably of intracisternal A-particle elements (IAPs). This induction, already present in wild-type cells, was markedly amplified in Irg1-deficient macrophages, placing IRG1 as a negative regulator of ERVs. A similar relationship was observed in human macrophages, where depletion of IRG1 boosted levels of HERVK under LPS.
ERV expression is classically known to be controlled by epigenetic and transcriptional regulatory mechanisms4. Accordingly, the authors first examined chromatin, but ATAC-seq revealed no differences between Irg1-KO and wild-type macrophages, indicating that the chromatin opening that accompanies activation proceeds independently of ITA. The effect was likewise independent of TET2, previously known to be inhibited by ITA3. Next, they applied nascent RNA sequencing on the same setup, also with no impact on transcriptional induction of repetitive RNAs. Instead, the higher ERV amounts were explained by an increased half-life of their RNAs. Interestingly, this increased stability was associated with a loss of m6A, an epitranscriptomic mark which had previously been described to target ERVs for degradation5. To identify the link between ITA and m6A, the authors performed protein pull-downs against ITA, which allowed them to identify the RNA m6A demethylase ALKBH5. Importantly, removing Alkbh5 from macrophages produced a destabilization of ERV transcripts even in the absence of ITA, and rendered them resistant to ITA supplementation. Finally, they selectively knocked down m6A RNA reader enzymes, finding YTHDF2 as a specific degrader of methylated ERV RNAs, identifying a novel IRG1–ITA–ALKBH5–YTHDF2 axis that mediates ERV transcript degradation in macrophages.
At the biochemical level, the authors demonstrated, by using in vitro assays with purified enzymes, that ITA directly inhibits ALKBH5 at concentrations several-fold below those it reaches in LPS-stimulated macrophages. Interestingly, inhibition by ITA was demonstrated to be specific to ALKBH5, as FTO, a related α-KG-dependent m6A demethylase6, was unaffected. The interaction between ITA and ALKBH5 was elegantly resolved by a co-crystal structure, revealing that ITA sits in the catalytic pocket, engaging key active-site residues. ITA binds ALKBH5 with an affinity comparable to that of α-KG, and an excess α-KG reversed inhibition, establishing substrate competition. Thus, ITA can function as a structurally selective regulator of an RNA-modifying enzyme.
This pathway also offers an interesting temporal perspective on the role of type I interferon in macrophage activation. IRG1 has previously been linked to early type I interferon responses7, yet the present study shows that its absence causes prolonged interferon signaling at later stages of macrophage activation. ERV transcripts in Irg1-deficient cells are reverse transcribed into DNA and accumulate in the cytosol, and that DNA rather than the RNA itself (MAVS depletion showed no effect) triggers cGAS-STING-dependent interferon responses, creating a feed-forward loop through IFN-β production. This late IFN-β production in Irg1-deficient cells is suppressed following reverse transcriptase inhibition or loss of cGAS. IRG1 may therefore have different functions across the macrophage activation trajectory: supporting aspects of the initial antimicrobial response while preventing endogenous retroelements from converting a transient response into chronic inflammation.
The physiological relevance of this mechanism is illustrated in kidney disease, a condition that was previously associated with ERV dysregulation8. In renal biopsies from patients with IgA nephropathy, macrophage IRG1 expression inversely correlated with HERVK abundance and positively correlated with kidney function. Myeloid-specific loss of Irg1 in mice aggravated ERV activation, type I interferon signaling, and fibrosis in two mouse models of kidney injury. Importantly, inhibition of retroviral reverse transcription alleviated disease, suggesting that ERV activity directly contributes to disease progression. ITA administration reduced ERV expression and renal fibrosis, whereas this protection disappeared when Alkbh5 was deleted in myeloid cells, genetically connecting the therapeutic effect of ITA to its newly identified target.
Several questions now emerge. What is the relative contribution of ITA's epigenetic3 versus RNA-centered effects to its anti-inflammatory function? Which physiological conditions render the IRG1–ITA–ALKBH5 axis insufficient to restrain ERV-driven inflammation? How broadly does the pathway operate across human ERV families, which differ substantially from the highly active murine IAP elements observed in this study? It will also be important to define when suppressing ERVs is beneficial, as controlled viral mimicry can contribute to antiviral and antitumor immunity, and also if this pathway can be modulated in humans in vivo.
More broadly, this study reframes the role of itaconate as more than a brake on inflammatory signaling. It reveals a novel mechanism by which metabolic reprogramming allows activated macrophages to control their own genomic remnants. By coupling an inflammation-induced metabolite to RNA modification and retroelement clearance, the proposed axis provides a mechanism by which macrophages can mount a strong response without allowing the molecular relics of the genome to maintain the response permanently switched on.

[1]

Huang, X. et al. Vita https://doi.org/10.15302/vita.2026.07.0060 (2026).

[2]

O’Neill, L.A.J. & Artyomov, M.N. Nat. Rev. Immunol. 19, 273–281 (2019).

[3]

Chen, L.L. et al. Nat. Cell Biol. 24, 353–363 (2022).

[4]

Karimi, M.M. et al. Cell Stem Cell 8, 676–687 (2011).

[5]

Chelmicki, T. et al. Nature 591, 312–316 (2021).

[6]

Jia, G.F. et al. Nat. Chem. Biol. 7, 885–887 (2011).

[7]

O’Carroll, S.M. et al. Nat. Metab. 6, 2060–2069 (2024).

[8]

Dhillon, P. et al. Nat. Commun. 14, 559 (2023).

RIGHTS & PERMISSIONS

The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Cite this article

Download citation ▾
Fabregat, C., Villar, J., Ginhoux, F.  Itaconate keeps endogenous retroviruses quiet  Vita https://doi.org/10.15302/vita.2026.09.0070 ()
AI Summary AI Mindmap
PDF (943KB)
Sections
Figures
References

54

Accesses

0

Citation

Detail

Recommended

AI思维导图

/

〈 〉