NET23/STING Promotes Chromatin Compaction from the Nuclear Envelope

Abstract

Changes in the peripheral distribution and amount of condensed chromatin are observed in a number of diseases linked to mutations in the lamin A protein of the nuclear envelope. We postulated that lamin A interactions with nuclear envelope transmembrane proteins (NETs) that affect chromatin structure might be altered in these diseases and so screened thirty-one NETs for those that promote chromatin compaction as determined by an increase in the number of chromatin clusters of high pixel intensity. One of these, NET23 (also called STING, MITA, MPYS, ERIS, Tmem173), strongly promoted chromatin compaction. A correlation between chromatin compaction and endogenous levels of NET23/STING was observed for a number of human cell lines, suggesting that NET23/STING may contribute generally to chromatin condensation. NET23/STING has separately been found to be involved in innate immune response signaling. Upon infection cells make a choice to either apoptose or to alter chromatin architecture to support focused expression of interferon genes and other response factors. We postulate that the chromatin compaction induced by NET23/STING may contribute to this choice because the cells expressing NET23/STING eventually apoptose, but the chromatin compaction effect is separate from this as the condensation was still observed when cells were treated with Z-VAD to block apoptosis. NET23/STING-induced compacted chromatin revealed changes in epigenetic marks including changes in histone methylation and acetylation. This indicates a previously uncharacterized nuclear role for NET23/STING potentially in both innate immune signaling and general chromatin architecture.

Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

“…In this respect, we noticed that nuclear STING partly co-localized with the phosphorylated histone ɣH2AX, suggesting a new role of STING in response to DNA damage. Although nuclear localization of STING had not been described before, its potential role in chromatin compaction in concert with other histones to potentiate immune signaling has been suggested [46]. IFI16, another DNA sensor commonly found in the cytosol, has been reported to re-localize into the nucleus after DNA or virus stimulation [47] and to associate with BRCA1 during DNA damage repair [48].…”

In silico synchronization reveals regulators of nuclear ruptures in lamin A/C deficient model cells

“…However, we have shown that nuclear ruptures are not lethal per se. Chromatin compaction may occur in a regulated manner independent of apoptosis, for instance by local remodeling of chromatin compaction-inducing proteins such as NET23 26 , as a result of local nuclear membrane loss and/or replenishment. Alternatively, since chromatin condensation has been associated with migratory phenotypes 27 and chromatin rapidly remodels upon external force application 28 29 30 , it may represent a protective response towards a mechanical insult.…”

Checkpoint Activation of an Unconventional DNA Replication Program in Tetrahymena

“…By analogy, studies in diploid maize cells have demonstrated that chromatin compaction can diminish propidium iodide fluorescence intensity [ 38 ]. Weakened interactions between chromosomes and the nuclear envelope promote chromatin compaction in cultured human cells, manifesting as aggregated chromatin clusters [ 39 ]. While we cannot distinguish between cause and effect at this time, our data suggest that the altered properties of macronuclear chromosomes described above are closely associated with epigenetic modifications on a genome-wide scale.…”