Intracellular localization of the BCL-2 family member BOK and functional implications

N Echeverry1, D Bachmann, F Ke

  • 1Institute of Pharmacology, University of Bern, Bern, Switzerland.

Insights

The pro-apoptotic protein BOK, a BCL-2 family member, activates mitochondrial apoptosis in a BAX/BAK-dependent manner. BOK localizes to the Golgi and ER, suggesting these organelles are key sites for its tumor suppressor functions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • BOK is a pro-apoptotic BCL-2 family member.
  • BOK resembles BAX and BAK in amino acid sequence.
  • BOK is hypothesized to be a tumor suppressor due to frequent genomic deletions in cancer.

Purpose of the Study:

  • To investigate the molecular functions of BOK.
  • To determine the localization and role of BOK in apoptosis.
  • To elucidate the relationship between BOK, BAX, and BAK in cell death.

Main Methods:

  • Enforced expression of BOK in cells with varying BAX/BAK status.
  • Analysis of BOK localization using microscopy.
  • Assessment of cell viability and organelle integrity upon BOK overexpression.
  • Evaluation of BOK-deficient cell response to Golgi/ER stress.

Main Results:

  • Enforced BOK expression activates the intrinsic apoptotic pathway in BAX/BAK-proficient cells.
  • BOK fails to induce apoptosis in cells lacking BAX and BAK.
  • BOK localizes to and inserts into Golgi and ER membranes via its C-terminal transmembrane domain.
  • BOK overexpression leads to early fragmentation of Golgi and ER compartments.
  • Bok-deficient cells exhibit abnormal responses to brefeldin A, a Golgi/ER stressor.

Conclusions:

  • BOK induces apoptosis in a BAX/BAK-dependent manner.
  • Major functions of BOK are associated with the Golgi and ER membranes.
  • BOK likely acts as a tumor suppressor through its functions at the Golgi and ER.

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
Nuclear Localization Signals and Import01:46

Nuclear Localization Signals and Import

Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of  2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as...
Cytoskeletal Linker Proteins - Plakins01:09

Cytoskeletal Linker Proteins - Plakins

Plakins are large proteins with binding domains for microtubules, microfilaments, intermediate filaments, and membrane-associated protein complexes at cell junctions. Plakin functions are evolutionarily conserved and are primarily involved in organizing the different components of the cytoskeleton by crosslinking them to each other and connecting them to the cell-matrix and cell adhesion complexes. They are also known to interact with signal transducers, serve as scaffolds for signaling...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Nuclear Protein Sorting01:34

Nuclear Protein Sorting

Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...