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ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia.

ABSTRACT: ARMC5 is implicated in several pathological conditions, but its function remains unknown. We have previously identified CUL3 and RPB1 (the largest subunit of RNA polymerase II (Pol II) as potential ARMC5-interacting proteins. Here, we show that ARMC5, CUL3 and RBX1 form an active E3 ligase complex specific for RPB1. ARMC5, CUL3, and RBX1 formed an active E3 specific for RPB1. Armc5 deletion caused a significant reduction in RPB1 ubiquitination and an increase in an accumulation of RPB1, and hence an enlarged Pol II pool in normal tissues and organs. The compromised RPB1 degradation did not cause generalized Pol II stalling nor depressed transcription in the adrenal glands but did result in dysregulation of a subset of genes, with most upregulated. We found RPB1 to be highly expressed in the adrenal nodules from patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) harboring germline ARMC5 mutations. Mutant ARMC5 had altered binding with RPB1. In summary, we discovered that wildtype ARMC5 was part of a novel RPB1-specific E3. ARMC5 mutations resulted in an enlarged Pol II pool, which dysregulated a subset of effector genes. Such an enlarged Pol II pool and gene dysregulation was correlated to adrenal hyperplasia in humans and KO mice.

SUBMITTER: Lao L

PROVIDER: S-EPMC9226510 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia.

Lao Linjiang L Bourdeau Isabelle I Gagliardi Lucia L He Xiao X Shi Wei W Hao Bingbing B Tan Minjia M Hu Yan Y Peng Junzheng J Coulombe Benoit B Torpy David J DJ Scott Hamish S HS Lacroix Andre A Luo Hongyu H Wu Jiangping J

Nucleic acids research 20220601 11

ARMC5 is implicated in several pathological conditions, but its function remains unknown. We have previously identified CUL3 and RPB1 (the largest subunit of RNA polymerase II (Pol II) as potential ARMC5-interacting proteins. Here, we show that ARMC5, CUL3 and RBX1 form an active E3 ligase complex specific for RPB1. ARMC5, CUL3, and RBX1 formed an active E3 specific for RPB1. Armc5 deletion caused a significant reduction in RPB1 ubiquitination and an increase in an accumulation of RPB1, and henc ...[more]

PMID: 35687106

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Project description:BackgroundPrimary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome characterized by the presence of bilateral secretory adrenal nodules. Recent studies have shown that primary bilateral macronodular adrenal hyperplasia is caused by combined germline and somatic mutations of the ARMC5 gene. Exophthalmos is an underappreciated sign of Cushing's syndrome.Case presentationA 52-year-old Chinese woman with progressively worsening bilateral proptosis presented to our hospital. Subsequently she was diagnosed as having primary bilateral macronodular adrenal hyperplasia and underwent bilateral laparoscopic adrenalectomy. Genomic deoxyribonucleic acid was isolated from lymphocytes as well as seven different adrenal nodules and the ARMC5 sequence was determined by Sanger sequencing. We identified one heterozygous ARMC5 germline mutation c.682C>T (p. Gln228*) and five heterozygous somatic mutations (c.310delG, c.347_357del11, c.267delC, c.283_289del7, and c.205-322del118) in five different adrenal nodules. All mutations are novel and were not found in any of the available online databases. To test whether the ARMC5 mutation induced messenger ribonucleic acid decay, real-time reverse transcriptase polymerase chain reaction was performed on patient and control adrenal tissue. We found that the adrenal cortex of our patient showed a low ARMC5 messenger ribonucleic acid expression compared with normal adrenal cortex, possibly as a result of nonsense-mediated messenger ribonucleic acid decay CONCLUSIONS: We demonstrated extensive genetic diversity of ARMC5 in a patient with primary bilateral macronodular adrenal hyperplasia that started with exophthalmos, which contributes to further understanding of the pathogenesis of this disease. Early recognition of atypical symptoms and screening for ARMC5 mutation in patients with primary bilateral macronodular adrenal hyperplasia has important clinical implications for the diagnosis and genetic counseling.

Dataset Information

ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia.

Publications

ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia.

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