Septin proteins are a distinct family of proteins, recognized as the fourth component of the cytoskeleton alongside actin filaments, microtubules, and intermediate filaments. They were first discovered almost 50 years ago in budding yeast (Saccharomyces cerevisiae) during studies of cell division. Researchers identified specific cell division cycle (CDC) genes whose protein products were associated with filamentous structures at the mother-bud neck. These proteins, later named septins, are highly conserved across nearly all eukaryotic cells, highlighting their widespread importance.
Septin Structure and Assembly
Individual septin proteins possess a guanosine triphosphate (GTP)-binding domain, allowing them to bind GTP, a molecule that provides energy for cellular processes. GTP binding enables septin monomers to form stable, non-polar hetero-oligomeric complexes. These complexes then polymerize end-to-end, forming linear filaments that lack distinct “plus” or “minus” ends, unlike actin or microtubules.
These filaments serve as building blocks, forming rods. These rods then assemble into more complex structures within the cell, such as rings, collars, hourglasses, and cage-like gauzes. The arrangement of these structures varies depending on the cell type or cell cycle stage.
The Role in Cell Division
Septins are extensively studied for their involvement in cytokinesis, the final stage of cell division where a parent cell divides into two daughter cells. In animal cells, septins accumulate at the cleavage furrow, an indentation that forms around the middle of the dividing cell. This recruitment often occurs early in telophase, orchestrated by scaffolding proteins like anillin, which localizes septins to the future division site.
At the cleavage furrow, septins assemble into a dynamic ring structure. This septin ring acts as a scaffold, providing a platform for recruiting other proteins, including components of the actomyosin contractile ring like myosin II. The septin ring provides structural support, ensuring the plasma membrane constricts efficiently and accurately. This coordinated action facilitates the complete separation of daughter cells, preventing errors in chromosome distribution.
Diverse Functions Within the Cell
Beyond their role in cell division, septins perform various other functions, demonstrating their versatility. They act as scaffolding platforms, recruiting specific proteins to particular locations on the cell membrane. This allows for the precise localization and interaction of molecular machinery involved in various cellular processes.
Septins also function as diffusion barriers, forming fence-like structures that restrict the movement of proteins and lipids within specific membrane domains. For instance, septin rings at the base of cellular protrusions like cilia or yeast buds can prevent proteins from freely diffusing between different membrane compartments, maintaining cellular compartmentalization. Septins are also involved in membrane remodeling, influencing the shape and curvature of cell membranes during processes such as vesicle trafficking and cell migration. Their ability to interact directly with membranes contributes to shaping the cell and facilitating dynamic cellular movements.
Septins and Human Disease
Dysfunction in septin proteins has been linked to several human diseases. In cancer, errors in septin-mediated cytokinesis can lead to failed cell division, resulting in cells with an abnormal number of chromosomes, a condition known as aneuploidy. Aneuploidy is a common characteristic of many cancerous cells and can contribute to tumor development and progression.
Emerging research also connects septin abnormalities to neurological disorders, including neurodegenerative conditions like Parkinson’s disease and Alzheimer’s disease. Septins are highly expressed in the brain and participate in processes such as synaptic vesicle trafficking and neurotransmitter release. Their involvement in protein aggregation, a hallmark of these diseases where misfolded proteins accumulate, suggests a role in disease progression.
Additionally, septins play a part in the cellular response to infectious diseases. Certain pathogens, such as the bacteria Listeria and Shigella, have evolved strategies to hijack the cell’s septin cage structures. By manipulating these septin assemblies, these pathogens can facilitate their own movement and spread from one cell to another, influencing the course of infection.