IQUB

IQUB is a structural component of the stalk of radial spoke 1 (RS1) in mammalian sperm flagella, essential for RS1 assembly, normal sperm motility, and male fertility (PMID:36417862, PMID:39849482). Within the RS1 complex, IQUB interacts with RSPH3 and recruits calmodulin under low-Ca²⁺ conditions to modulate the RSPH3/p-ERK1/2 signaling axis, and its deficiency causes selective RS1 loss with secondary downregulation of inner dynein arms DNAH7 and DNAH12 (PMID:36355624, PMID:39849482). IQUB also functions as a downstream effector of ARL3 in limiting primary cilia length; its depletion leads to cilia over-elongation, and re-expression rescues this phenotype (PMID:21289087, PMID:38457249). Homozygous loss-of-function IQUB mutations cause asthenoteratozoospermia and male infertility in humans (PMID:39849482).

1. 2011 Medium

   Whether IQUB had any ciliary function was unknown; siRNA knockdown established that IQUB limits cilia length and participates in Hedgehog signaling, identifying it as a ciliary regulatory factor.

   Evidence siRNA knockdown with cilia length quantification and Gli-luciferase Hedgehog assay in three mammalian cell lines

   PMID:21289087

   Open questions at the time

   • Mechanism by which IQUB controls cilia length was not defined
   • Whether IQUB acts in motile cilia/flagella was untested
   • Upstream regulators of IQUB expression unknown
2. 2018 Medium

   Whether IQUB influenced proliferative signaling outside the cilium was unknown; overexpression and knockdown showed IQUB activates the Akt/GSK3β/β-catenin pathway to promote breast cancer cell proliferation and migration.

   Evidence Gain- and loss-of-function with pharmacological epistasis (LiCl, MG-132) in MCF-7 and MDA-MB-231 breast cancer cells

   PMID:29968965

   Open questions at the time

   • Relevance to non-cancer physiology unclear
   • No in vivo tumor model validation
   • Mechanism linking IQUB's IQ domains to Akt activation not identified
3. 2022 High

   The role of IQUB in motile flagella was unknown; Iqub knockout mice revealed that IQUB is essential for assembly of the entire radial spoke 1 in sperm flagella, causing male infertility, while being dispensable for RS1 in tracheal cilia.

   Evidence Iqub knockout mouse with cryo-electron tomography, transmission EM, and proteomics of sperm RS1

   PMID:36417862

   Open questions at the time

   • Precise position of IQUB within RS1 architecture was not resolved
   • Why tracheal cilia RS1 is independent of IQUB was unexplained
   • Downstream signaling consequences of RS1 loss not addressed
4. 2023 Medium

   How IQUB contributes to RS1 assembly at the molecular level was unclear; interaction mapping and signaling analysis showed IQUB binds RSPH3 and calmodulin, and recruits calmodulin under low-Ca²⁺ conditions to inhibit the RSPH3/p-ERK1/2 complex, linking radial spoke assembly to an AKAP-like signaling module.

   Evidence Yeast two-hybrid screen, co-immunoprecipitation, Iqub KO/KI mouse models, Western blot for p-ERK1/2

   PMID:36355624

   Open questions at the time

   • Calmodulin recruitment mechanism lacks direct structural validation
   • Whether p-ERK1/2 dysregulation is a cause or consequence of RS1 disassembly is ambiguous
   • In vitro reconstitution of the IQUB–calmodulin–RSPH3 complex not performed
5. 2024 Medium

   Whether IQUB's cilia-length role was connected to known ciliopathy pathways was unknown; IQUB was identified as a downstream effector of ARL3, with rescue of elongated cilia in ARL3-mutant patient fibroblasts confirming IQUB as the functional mediator.

   Evidence Patient-derived immortalized fibroblasts with ARL3 compound heterozygous mutations, RNA-seq, proteomics, IQUB re-expression rescue

   PMID:38457249

   Open questions at the time

   • Mechanism by which ARL3 regulates IQUB expression or stability not defined
   • Whether this pathway operates in motile cilia/flagella is untested
   • Single patient genotype limits generalizability
6. 2025 High

   The precise structural position of IQUB in RS1 and its loss-of-function consequences in humans were undefined; a human frameshift mutation combined with mouse KO showed IQUB forms part of the RS1 stalk, and its loss selectively eliminates RS1 with secondary loss of inner dynein arms DNAH7 and DNAH12.

   Evidence Whole-exome sequencing of infertile patient, Iqub−/− mouse, mass spectrometry, EM, structural modeling

   PMID:39849482

   Open questions at the time

   • Atomic-resolution structure of the RS1 stalk with IQUB is lacking
   • How RS1 loss causes secondary inner dynein arm downregulation is mechanistically unresolved
   • Whether IQUB mutations contribute to female subfertility is unknown

• How IQUB's dual roles in primary cilia length regulation (via ARL3) and motile flagella RS1 assembly are coordinated, and the structural basis of IQUB-calmodulin interaction within the RS1 stalk, remain unresolved.
• No atomic structure of IQUB or IQUB-containing RS1 complex
• Tissue-specific regulation of IQUB's cilia-length vs. RS1-assembly functions not understood
• Relationship between IQ-domain calmodulin binding and RS1 structural integrity undefined