The Nuclear Envelope Protein Emerin Binds Directly to Histone Deacetylase 3 (HDAC3) and Activates HDAC3 Activity

Chuang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

115

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.T he endoplasmic reticulum (ER) plays important roles in cellular functions, including synthesis of proteins and regulation of Ca 2+ signaling between the ER and plasma membrane (1) and between the ER and mitochondria (2-4). However, because the ER interacts with other organelles in the cell, other functions related to the ER remain to be uncovered.The sigma-1 receptor (Sig-1R) (5-8) is an ER chaperone molecule that resides at the ER-mitochondrion interface referred to as the mitochondria-associated ER membrane (MAM), where the Sig-1R ensures proper ER-mitochondrion Ca 2+ signaling for cellular survival (3, 9), as well as sustains the activity of an ER stress sensor IRE1 at the MAM (10). The Sig-1R can translocate from the MAM to plasma membrane of the cell to regulate ion channels and receptors on the plasma membrane (8,(11)(12)(13)(14). Cocaine is a Sig-1R agonist (3) that causes the dissociation of Sig-1R from its cognate binding partner BiP (3,8), and consequently the translocation of Sig-1Rs to the plasma membrane, where Sig-1Rs interact with voltage-gated potassium channel subfamily A member 2 (Kv1.2) to shape the neuronal and behavioral responses to cocaine (15).Cocaine also causes the translocation of Sig-1Rs from the ER to the nucleus (16), where Sig-1Rs are shown to be present at the nuclear envelope (NE) (17). H...

“…(BAF) (23,30). Emerin also interacts with HDAC3 to regulate the HDAC3 localization and activity at the nuclear periphery (24,31).…”

Section: Significancementioning

confidence: 99%

Section: Sig-1r Apparently Interacts Specifically With a Ne Integral mentioning

confidence: 99%

mentioning

confidence: 99%

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Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

Chuang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

115

Journal of Biological Chemistry

“…S54F is a "special" EDMD-causing mutation that does not disrupt emerin expression or localization yet still causes EDMD (78). S54F disrupts direct binding to two (of eight tested) partners in vitro: mRNA splicing/processing factor Btf (108,109) and HDAC3 (28). Emerin stimulates HDAC3 deacetylase activity; hence, EDMD disease may reflect insufficient HDAC3-de-pendent gene silencing (28).…”

Section: Discussionmentioning

confidence: 99%

“…For example, emerin and LAP2␤ each directly bind HDAC3 (histone deacetylase 3), a chromatin-silencing enzyme, and stimulate HDAC3 activity (28,29). At the IgH locus, the regulated tethering of lamina-associated domains of chromosomes is mediated by DNA sequence repeats bound to a transcriptional repressor (cKrox) in complex with HDAC3 and LAP2␤ and is established during mitosis (30).…”

mentioning

confidence: 99%

O-Linked β-N-Acetylglucosamine (O-GlcNAc) Regulates Emerin Binding to Barrier to Autointegration Factor (BAF) in a Chromatin- and Lamin B-enriched “Niche”

Berk

Maitra

Dawdy

et al. 2013

Background: Nuclear membrane protein emerin binding to nuclear intermediate filaments (lamins) and BAF contributes to forming a nuclear "lamina" structure. Results: Emerin is O-GlcNAc-modified at eight sites: two (Ser-53 and Ser-54) influence further O-GlcNAcylation, and one (Ser-173) regulates association with BAF in the chromatin/lamin B "niche." Conclusion: O-GlcNAc transferase, a nutrient-responsive enzyme, regulates emerin. Significance: Emerin hyper-O-GlcNAcylation may contribute to cardiomyopathy and other conditions.

Choreography of lamina‐associated domains: structure meets dynamics

Alagna,

Thomas,

Wilson

et al. 2023

FEBS Letters

Lamina‐associated domains are large regions of heterochromatin positioned at the nuclear periphery. These domains have been implicated in gene repression, especially in the context of development. In mammals, LAD organization is dependent on nuclear lamins, inner nuclear membrane proteins, and chromatin state. In addition, chromatin readers and modifier proteins have been implicated in this organization, potentially serving as molecular tethers that interact with both nuclear envelope proteins and chromatin. More recent studies have focused on teasing apart the rules that govern dynamic LAD organization and how LAD organization, in turn, relates to gene regulation and overall 3D genome organization. This review highlights recent studies in mammalian cells uncovering factors that instruct the choreography of LAD organization, re‐organization, and dynamics at the nuclear lamina, including LAD dynamics in interphase and through mitotic exit, when LAD organization is re‐established, as well as intra‐LAD subdomain variations.