FOXK1

Description

The FOXK1 (forkhead box K1) is a protein-coding gene located on chromosome 7.

Forkhead box protein K1 is a transcription factor of the forkhead box family that in humans is encoded by the FOXK1 gene. During starvation, in type 2 diabetes, in rapidly dividing cells during embryogenesis, in tumors (Warburg effect) and during T cell proliferation, aerobic glycolysis is induced to produce the building block to sustain growth. FOXK1 is one of the transcription factors managing the passage from the normal cellular respiration (complete glucose oxidation) to generating ATP and intermediaries for many other biochemical pathways. FOXK1 and its closely relate sibling FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria—instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.

FOXK1, also known as Myocyte nuclear factor, is a transcriptional regulator involved in diverse cellular processes, including glucose metabolism, aerobic glycolysis, muscle cell differentiation, and autophagy. It recognizes and binds to the forkhead DNA sequence motif (5'-GTAAACA-3') and acts as both a transcription activator and repressor, depending on the cellular context. Together with FOXK2, FOXK1 plays a key role in metabolic reprogramming towards aerobic glycolysis, promoting the expression of glycolytic enzymes such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR), and lactate dehydrogenase while simultaneously suppressing further oxidation of pyruvate in the mitochondria by upregulating pyruvate dehydrogenase kinases PDK1 and PDK4. FOXK1 is likely involved in gluconeogenesis during overnight fasting, utilizing lactate from white adipose tissue and muscle as the primary substrate. It is also involved in mTORC1-mediated metabolic reprogramming, translocating into the nucleus in response to mTORC1 signaling to regulate the expression of genes associated with glycolysis and downstream anabolic pathways, such as HIF1A, thereby controlling glucose metabolism. In collaboration with FOXK2, FOXK1 acts as a negative regulator of autophagy in skeletal muscle, entering the nucleus during starvation to repress the expression of autophagy genes and prevent the proteolysis of skeletal muscle proteins. FOXK1 is a crucial transcriptional regulator of the myogenic progenitor cell population in skeletal muscle, binding to the upstream enhancer region (CCAC box) of the myoglobin (MB) gene to modulate this cell population. It promotes muscle progenitor cell proliferation by repressing FOXO4 transcriptional activity, thus inhibiting myogenic differentiation. FOXK1 plays a role in remodeling processes of adult muscles in response to physiological stimuli, ensuring the proper temporal orchestration of molecular and cellular events during muscle repair. It inhibits myogenic differentiation by suppressing MEFC activity. FOXK1 positively regulates Wnt/beta-catenin signaling by translocating DVL into the nucleus, reduces virus replication by binding to the interferon stimulated response element (ISRE) to promote antiviral gene expression, and is an accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex, recruiting it to specific FOXK1-bound genes. It interacts with SIN3A and SIN3B to repress transcription and is a component of SIN3A-containing multiprotein complexes. FOXK1 interacts with FOXO4 and MEF2C, inhibiting their transactivation activity, and with YWHAE/14-3-3-epsilon when phosphorylated, leading to cytoplasmic sequestration and impaired DNA binding. It also interacts with FHL2, SRF, DVL2, DVL3, and BAP1, promoting DVL2 nuclear translocation and acting as an accessory component of the PR-DUB complex along with BAP1, ASXL1/2/3, MBD5/6, KDM1B, HCFC1, and OGT.

FOXK1 is also known as FOXK1L.

Associated Diseases

WES Whole Exome Sequencing