Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn

Abstract

Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1/Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn-deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn-deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt–Hogg–Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity

“…Our investigation of the hamel allele reinforces the nonredundant roles of FNIP1 in B-cell development (7,8), skeletal muscle composition (9), and cardiac function (6). We reveal that BCL2 overexpression can partially, but not entirely, rescue B-cell development in the absence of FNIP1, and we provide evidence that FNIP1 is an endogenous negative regulator of AMPK.…”

“…5B) but observed no differences in total or γ2-specific activity between wild-type and mutant (Fig. 5B), suggesting that Fnip1 and Fnip2 may be functionally redundant in the liver, as they are in the kidney (6).…”

“…FLCN is a nonredundant component of the FLCN/FNIP1/FNIP2 complex, whereas FNIP1 and FNIP2 appear to be functionally redundant in several tissues. This distinction is illustrated by the fact that kidney-specific deletion of mouse Flcn or compound deletion of Fnip1 and Fnip2 is sufficient to cause renal tumors, and yet deletions of Fnip1 or Fnip2 alone are not (6). This redundancy is consistent with the equivalent expression of Fnip1 and Fnip2 mRNA in kidney tissue (6).…”

“…This distinction is illustrated by the fact that kidney-specific deletion of mouse Flcn or compound deletion of Fnip1 and Fnip2 is sufficient to cause renal tumors, and yet deletions of Fnip1 or Fnip2 alone are not (6). This redundancy is consistent with the equivalent expression of Fnip1 and Fnip2 mRNA in kidney tissue (6). In contrast, FNIP1 is nonredundant in other tissues, including bone marrow, myocardium, and skeletal muscle: all of which express relatively more Fnip1 than Fnip2 (6-9).…”

“…In one report (9), FNIP1-deficient skeletal muscle exhibited enhanced phosphorylation of the catalytic α subunit of AMPK (at residue Thr172-a requirement for its activation) (9) but reduced phosphorylation in another (6). Similarly, mTOR activity was reported to be increased in B-cell precursors in one Fnip1 mutant (8) but normal in a second model (7).…”