FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency

Abstract

Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D. Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function. Evidence from murine models suggests that FNIP1 loss disrupts immune cell development and mitochondrial homeostasis. However, FNIP1 deficiency in humans remains incompletely characterized, and its full phenotypic spectrum is likely underestimated. Notably, FNIP1-deficient patients exhibit immunological and hematological abnormalities, immune dysregulation, and metabolic perturbations, emphasizing its role in cellular adaptation to stress. Understanding the mechanistic basis of FNIP1 dysfunction in human tissues will be critical for delineating its contributions to immune and metabolic disorders and identifying targeted interventions.

Keywords: FNIP1 deficiency; agammaglobulinemia; hypertrophic cardiomyopathy; inborn error of immunity; neutropenia; primary immunodeficiency.

Figure 1

Protein domains, functional roles, and tissue-specific expression of FNIP1. (A) Schematic representation of FNIP1 protein structure and post-translational modifications. FNIP1 contains distinct domains, including longin, degron, and DENN-like domains. FNIP1 undergoes AMPK-dependent phosphorylation at serine residues S220, S230, S232, S261, and S593, regulating its function in metabolic sensing. Additional casein kinase 2 (CK2)-mediated phosphorylation at S938, S939, S941, S946, and S948 facilitates HSP90 inhibition and client protein activation. Conversely, protein phosphatase 5 (PP5)-mediated dephosphorylation allows for O-GlcNAc transferase (OGT)-dependent glycosylation of S938, thereby preventing HSP90 interaction and leading to K1119 ubiquitination and proteasomal degradation. The degron motif (C580, C582, and C585) enables FEM1B binding and FNIP1 ubiquitylation, facilitating degradation in response to reductive stress. (B) Tissue-specific FNIP1 RNA expression. Expression levels (nTPM) of FNIP1 transcripts across various human tissues. FNIP1 shows high expression in immune-related tissues, including the thymus, spleen, and bone marrow, as well as in metabolically active tissues such as the kidney and liver. (C) Tissue-specific FNIP1 protein expression. Protein expression levels, categorized as high, medium, low, or not detected with strong FNIP1 presence in immune and metabolic active tissues (https://v22.proteinatlas.org/ENSG00000217128-FNIP1/tissue, accessed on 4 March 2025).

Figure 2

FNIP1 cellular signaling and metabolism. FNIP1, in complex with folliculin (FLCN), functions as a GAP (GTPase-activating protein) for RagC/D to regulate mTORC1 activity at the lysosome. Under low energy conditions (high AMP/low ATP) ①, FNIP1 is phosphorylated by AMPK, which prevents RagC activation ② and inhibits mTORC1 signaling. This results in the activation of TFE family transcription factors (TFEB and TFE3) ③④, which drive lysosomal ⑤ and mitochondrial biogenesis ⑥ via PGC1α and PGC1β transcription. Created in BioRender. Iritani, B. (2025), https://BioRender.com/f18p969, accessed on 4 March 2025.

Figure 3

Clinical features of FNIP1 deficiency by organ system. Common clinical findings are shown by the affected organ system. Vectors from Freepik. LV HCM = left ventricular hypertrophic cardiomyopathy. WPW = Wolff–Parkinson–White syndrome.