DHHC3-dependent S-Acylation of CRY1 regulates its subcellular localization and repressor function in the circadian clock

Jun 4, 2026bioRxiv : the preprint server for biology

DHHC3-controlled fat attachment affects CRY1’s location and role in the body clock

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Abstract

Cryptochrome 1 (CRY1) undergoes a novel post-translational modification known as S-acylation.

S-acylation of CRY1 is necessary for its nuclear import and interaction with essential clock components.
Four cysteine residues have been identified as sites for S-acylation on CRY1.
DHHC3 is established as the primary protein acyltransferase responsible for CRY1 S-acylation.
Impairment of CRY1 S-acylation through cysteine mutagenesis or DHHC3 deletion disrupts CRY1 repressor function.
Disruption of CRY1 repressor function leads to impairment of cellular circadian rhythms.
S-acylation is positioned as a critical modification for circadian clock function.

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The circadian clock is essential for maintaining cellular homeostasis and physiological fitness. At the molecular level, core clock proteins function via transcriptional-translational feedback loops in the cellular oscillator, and are highly regulated by post-translational modifications. Our unbiased screening of core clock proteins revealed that Cryptochrome 1 (CRY1), the central transcriptional repressor in the circadian clock, undergoes a novel post-translational modification known as S-acylation. We show that this reversible lipidation of CRY1 is required for its nuclear import and interaction with key clock components. Further, we mapped four cysteine residues as CRY1 S-acylation sites and identified DHHC3 as the primary protein acyltransferase for CRY1. Importantly, loss of CRY1 S-acylation, either via cysteine mutagenesis or genetic deletion of DHHC3, impaired CRY1 repressor function and consequently cellular circadian rhythms, suggesting that dynamic S-acylation couples cytoplasmic regulation of CRY1 and its transcriptional repressor function in the nucleus. Together, our findings identify S-acylation as a previously unknown post-translational modification of CRY1 critical for circadian clock function and establish DHHC3 as a pivotal circadian regulatory enzyme. Targeting CRY1 S-acylation or its regulatory enzymes may constitute an innovative therapeutic approach against clock-associated diseases.

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DHHC3-dependent S-Acylation of CRY1 regulates its subcellular localization and repressor function in the circadian clock

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