Abstract
The crosstalk between actin and actin-related proteins (Arps), namely Arp2 and Arp3, plays a central role in facilitating actin polymerization in the cytoplasm and also in the nucleus. Nuclear F-actin is required for transcriptional regulation, double-strand break repair, and nuclear organization. The formation of nuclear F-actin is highly dynamic, suggesting the involvement of positive and negative regulators for nuclear actin polymerization. While actin assembly factors for nuclear F-actin have been recently described, information about inhibitory factors is still limited. The actin-related protein Arp4 which is predominantly localized in the nucleus, has been previously identified as an integral subunit of multiple chromatin modulation complexes, where it forms a heterodimer with monomeric actin. Therefore, we tested whether Arp4 functions as a suppressor of nuclear F-actin formation. The knockdown of Arp4 (Arp4 KD) led to an increase in nuclear F-actin formation in NIH3T3 cells, and purified Arp4 potently inhibited F-actin formation in mouse nuclei transplanted into Xenopus laevis oocytes. Consistently, Arp4 KD facilitated F-actin-inducible gene expression (e.g., OCT4) and DNA damage repair. Our results suggest that Arp4 has a critical role in the formation and functions of nuclear F-actin.
Highlights
Actin has structural and regulatory roles in the cytoplasm and the nucleus
For visualization of nuclear F-actin, an anti-actin-chromobody tagged with a nuclear localization signal and mCherry was used
Arp4 by RNA interference (Figure S1) and observed nuclear F-actin using an anti-actin-chromobody tagged with a nuclear localization signal [12]
Summary
Actin has structural and regulatory roles in the cytoplasm and the nucleus. The nuclear import of actin is regulated by importin 9 [1], and exportin 6 exports actin to the cytoplasm [2]. Nuclear G-actin is included in multiple chromatin remodeling and histone modification complexes, and is involved in the regulation of genome functions [3]. Nuclear F-actin plays various roles in the nucleus, including in transcriptional regulation [6]. The formation of nuclear F-actin decreases the nuclear G-actin pool, causing activation of SRF target genes through the retention of MAL in the nucleus [4]. Among the 10 Arp subfamilies, Arp4–Arp are found predominantly in the nucleus [3] These nuclear Arps reside in multiple chromatin remodeling and histone modification complexes, in most cases, together with actin, suggesting that actin regulation by nuclear Arps occurs in the nucleus. Our finding implies a novel role for Arp in regulating the dynamics and function of nuclear actin
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