C1QTNF4

C1QTNF4 Full Name

C1q and tumor necrosis factor related protein 4

C1QTNF4 Introduction

C1QTNF4 belongs to the C1q/TNF-related protein (CTRP) family, whose members are characterized by the structural hallmark of a C1q globular domain and a TNFα homotrimeric motif. Distinct from other family members, C1QTNF4 features a unique "double C1q" conformation formed by two C1q-like domains connected via a short linker peptide. This structure enables its ability to form higher-order oligomers through covalent bonds. Tissue expression profiling reveals that C1QTNF4 exhibits a broad yet specific distribution pattern. In humans, the gene is clearly expressed in brain tissue, adipose tissue, hematopoietic stem cells, and progenitor cells. A notable interspecies difference in its expression pattern is that, unlike in mouse models, C1QTNF4 is specifically enriched in human hematopoietic progenitors. Expression of C1QTNF4 is sexually dimorphic (sexually biased with significant difference between males and females, according to GTEx RNA sequencing data), which may imply regulation by sex hormones.

Figure 1. Structural and functional characterization of C1QTNF4 p.His198Gln substitution. (Source: Pullabhatla V, et al. 2018)

Functional studies of C1QTNF4 are still in their infancy. In immune regulation, C1QTNF4 has been reported to act as a specific receptor for nucleolin. C1QTNF4 modulates innate immune signal transduction via the interaction with nucleolin, suggesting a role in pathogen recognition or autoimmune surveillance. The report also offered a molecular explanation for its aberrant expression in SLE patients (systemic lupus erythematosus, an autoimmune disease) where C1QTNF4 expression is significantly up-regulated in the PBMCs, possibly aggravating the disease via a type I interferon response. In contrast, there are contradictory findings about its inflammatory regulatory role: In vitro experiments identified both pro- and anti-inflammatory phenotypes for C1QTNF4. These may be cell type dependent, or may reflect selective activation of distinct branches of downstream signaling.

Regarding metabolic functions, although other CTRP family members such as CTRP1 and CTRP3 have been confirmed to participate in fatty acid oxidation, glucose homeostasis, and aldosterone synthesis, direct evidence for C1QTNF4's role in metabolic regulation remains limited. The disease association profile of C1QTNF4 extends from autoimmunity to the metabolic-cardiovascular axis, though the strength of causal and clinical correlation evidence is uneven. In terms of autoimmune disease, the evidence is most solid in SLE: multiple independent cohort studies have established a positive correlation of C1QTNF4 expression with disease activity, and it may be involved in the subtyping of the disease as part of the interferon gene signature. In the cardiovascular risk phenotype, although there is no direct evidence for C1QTNF4's role in atherosclerosis to date, one of its family members, CTRP1, is involved in vascular smooth muscle cell proliferation and migration and C1QTNF4 is expressed in vascular wall cells, therefore a paracrine role for C1QTNF4 in vascular remodeling can be anticipated. All of the observed associations with metabolic disease to date have been the result of indirect inferences: expression profiling in adipose tissue found C1QTNF4 to be downregulated in obese mouse models, and expression of C1QTNF4 in preadipocytes negatively correlated with markers of adipocyte differentiation. Therefore, it is conceivable that C1QTNF4 has a protective role in the inflammation of obesity, although not yet tested in humans. Preliminary studies in the tumor microenvironment suggest that C1QTNF4 may affect cancer-related inflammation through regulation of the polarization state of tumor-associated macrophages, but the mechanism and clinical significance are still far from clear.

Alternate Names for C1QTNF4

C1QTNF4; C1q and tumor necrosis factor related protein 4; CTRP4; ZACRP4; complement C1q tumor necrosis factor-related protein 4; complement-c1q tumor necrosis factor-related protein 4;

• 1. Sch?ffler A, et al. CTRP family: linking immunity to metabolism. Trends Endocrinol Metab. 2012 Apr;23(4):194-204.
  2. Pullabhatla V, et al. De novo mutations implicate novel genes in systemic lupus erythematosus. Hum Mol Genet. 2018 Feb 1;27(3):421-429.