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Disruption of Kir2.1 function can cause Andersen-Tawil syndrome type 1 (ATS1), a multisystem channelopathy that predisposes patients to ventricular dysrhythmias and increases the risk of sudden cardiac death. Kir2.1 activity depends on interactions with the membrane phospholipid PIP2, and these interactions can be weakened by genetic mutations or posttranslational modifications. Here, we identify a shared mechanism by which hypoxia-induced SUMOylation and a heterozygous ATS1-linked variant, R67Q, independently and cooperatively suppress Kir2.1 function. We found that SUMOylation reduces Kir2.1 current in a stoichiometric manner, with up to two SUMO proteins per channel tetramer diminishing current by \u223c24% each. Channels containing heterozygous R67Q subunits are disproportionately sensitive to hypoxic suppression. Inhibiting the SUMO pathway with TAK-981 prevents this suppression and enhances current in both WT and R67Q-containing channels. Further analysis revealed that both SUMOylation and the R67Q mutation reduce the stability of Kir2.1\u2013PIP2 interactions, indicating a convergent gating defect. These findings support a two-hit model of channel dysfunction, in which a genetic variant and an environmental stressor act through a common structural mechanism to impair Kir2.1 gating. By identifying PIP2 destabilization as the point of convergence, this work provides new insight into how stress-sensitive channelopathies arise and suggests that SUMO pathway inhibition may offer a strategy to restore function under adverse physiological conditions.<\/jats:p>","DOI":"10.1085\/jgp.202513837","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T06:20:28Z","timestamp":1758608428000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["SUMOylation and an ATS1 variant converge to disrupt PIP2-dependent gating of Kir2.1"],"prefix":"10.1085","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0633-1572","authenticated-orcid":true,"given":"Aishwarya","family":"Chandrashekar","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t5xt781","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmacy and Pharmaceutical Sciences, Bouv\u00e9 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