ARMC5, a cytoplasmic protein encoded by a gene rich in armadillo (ARM) repeat sequences, has emerged as a critical regulator of cellular processes, with implications spanning tumor suppression, endocrine disorders, and immune modulation. Ubiquitously expressed across human tissues, ARMC5 lacks enzymatic activity but mediates protein-protein interactions through its ARM repeats and BTB/POZ domain. These structural features enable it to act as a scaffold for ubiquitin ligase complexes, influencing protein degradation via the ubiquitin-proteasome system (UPS). Initially identified as a tumor suppressor linked to bilateral macronodular adrenocortical disease (BMAD), ARMC5’s role has expanded to include associations with meningiomas, primary aldosteronism (PA), renal cell carcinoma (RCC), and embryonic development.

Germline and somatic mutations in ARMC5 disrupt its tumor-suppressive functions, often following Knudson’s two-hit hypothesis. In BMAD, pathogenic variants occur in ~50% of cases, leading to adrenal hyperplasia and cortisol overproduction. These mutations cluster in ARM repeats or BTB domains, truncating the protein or impairing interactions with partners like CUL3 and RPB1. Dysregulated ARMC5 destabilizes steroidogenic enzymes and promotes adrenal cell accumulation, paradoxically causing hypercortisolism despite reduced per-cell cortisol synthesis. Clinical phenotypes vary: carriers often present with metabolic complications, earlier disease onset, and familial clustering, necessitating genetic screening for early diagnosis. Beyond BMAD, ARMC5 mutations correlate with meningiomas, particularly in patients with concurrent adrenal pathology. Somatic mutations in meningioma tissues suggest biallelic inactivation drives tumorigenesis, though mechanisms linking adrenal steroid excess to intracranial tumors remain unclear.

In PA, ARMC5 variants are prevalent among African Americans, correlating with hypertension and altered glucose metabolism. While β-catenin-driven WNT signaling is a known PA pathway, ARMC5’s ARM repeats hint at analogous regulatory roles, though direct evidence is lacking. Similarly, reduced ARMC5 expression in RCC tissues implicates UPS dysregulation in renal carcinogenesis, with USP7-mediated deubiquitination stabilizing ARMC5 to modulate proliferation. These findings underscore tissue-specific ARMC5 functions—pro-apoptotic in adrenal cells yet pro-proliferative in renal contexts.

Embryonic studies reveal ARMC5’s indispensability: knockout mice exhibit lethal developmental defects, while heterozygotes show delayed adrenal insufficiency or late-onset hyperplasia. Immune modulation is another frontier: ARMC5 deficiency impairs T-cell differentiation and apoptosis, attenuating autoimmune responses but increasing infection susceptibility. This duality mirrors its role in BMAD, where mutations drive adrenal hyperplasia while suppressing immune activity, highlighting context-dependent functionality.

Clinically, ARMC5 mutations redefine BMAD as a genetic disorder, shifting diagnostic paradigms toward germline testing and familial screening. Over 100 pathogenic variants are documented, predominantly nonsense or frameshift mutations causing loss of function. Genotype-phenotype correlations remain elusive, necessitating larger cohorts to clarify variant impacts. Therapeutic strategies targeting ARMC5 interactions, such as UPS inhibitors or CRISPR-based editing, hold promise but require mechanistic insights into its signaling networks.

Structurally, ARMC5’s homology to β-catenin suggests roles in conserved pathways like WNT signaling. Its ARM repeats form α-superhelices for binding partners, while the BTB domain recruits E3 ligases for substrate ubiquitination. Interactions with RNA Pol II and CUL3 implicate ARMC5 in transcriptional regulation and protein turnover, though precise pathways are uncharted. Structural studies using AlphaFold predictions align ARMC5 with β-catenin, reinforcing its potential as a signaling hub.

Future research must address ARMC5’s paradoxical roles—suppressing tumors in some contexts while fostering proliferation in others. Single-cell sequencing could unravel heterogeneity in ARMC5-expressing cells, while biomarker-driven therapies may exploit its tissue-specific interactions. Ethical and regulatory challenges, particularly in autologous cell therapies, demand interdisciplinary collaboration. As a linchpin connecting genetic, endocrine, and oncological research, ARMC5 exemplifies the complexity of molecular medicine, offering avenues for precision diagnostics and targeted interventions.
DOI: 10.1007/s11684-024-1108-0