Septins: The Fourth Component of the Cytoskeleton

While many of the cell’s components are well-documented, a family of proteins called septins has steadily emerged as versatile and dynamic organizers. Often considered the fourth component of the cytoskeleton, septins are foundational to some of the most basic processes of life. They act as the cell’s architects, building barriers, platforms, and rings that guide cellular events and help us understand the intricate choreography inside every eukaryotic cell.

The Fourth Component of the Cytoskeleton

The cell’s shape and internal organization are maintained by a network of protein filaments known as the cytoskeleton, long understood to have three main elements: actin filaments, microtubules, and intermediate filaments. A fourth class of proteins, the septins, is now recognized as an integral part of this system. Septins are a family of proteins that bind to guanosine triphosphate (GTP), allowing them to act as molecular switches that change their function.

Originally discovered in budding yeast during the 1970s, septins were identified because mutations in their genes caused cells to fail to separate properly during cell division, or cytokinesis.

Unlike the other cytoskeletal components, which form long polar filaments, septins assemble into more complex structures like rings and gauzes, allowing them to perform distinct roles. Human cells contain 13 different septins, organized into four distinct groups.

Septin Structure and Assembly

Septin proteins engage in a hierarchical assembly process to form elaborate structures. The foundational building blocks are stable, rod-shaped core complexes, which in human cells contain either six or eight septin proteins in a specific arrangement. These core particles are nonpolar, a key departure from the polarity of actin and microtubules.

These core complexes are recruited from the cytoplasm to cellular membranes. Once concentrated on a two-dimensional surface like the plasma membrane, these rods polymerize by joining end-to-end. This elongates the rods into long, flexible filaments in a dynamic process that allows for both growth and reorganization.

These filaments can then associate with one another to create even more complex structures. Depending on the cellular context and location, they can be bundled together, woven into mesh-like arrangements known as gauzes, or curved into distinct rings. These structures are often found at sites of high membrane curvature or where specific cellular events are taking place.

Cellular Roles of Septins

One of the most well-documented roles for septins is in cytokinesis, the final stage of cell division where one cell physically splits into two. During this process, septins assemble into a ring at the cleavage furrow, the indentation where the cell will divide. This ring works with other proteins to organize the machinery needed for contraction, ensuring the division is completed successfully.

Beyond cell division, septins act as molecular scaffolds, creating platforms that recruit other proteins to specific locations on the cell membrane. By assembling at a site, they create a hub that concentrates components for processes like membrane remodeling or signaling. For example, in developing neurons, septins are important for guiding microtubules into new branches, and they also interact directly with the actin cytoskeleton.

Septins also form diffusion barriers that function like molecular fences to compartmentalize the cell membrane. They assemble into tight rings at the base of specialized structures, such as primary cilia or the flagella of sperm. These septin rings prevent the free movement of membrane-bound proteins, ensuring these compartments maintain their unique protein composition.

Implications in Human Disease

When septin function goes awry, it can contribute to diseases ranging from cancer to neurodegeneration. Because septins are integral to cell division, errors in their expression or assembly can lead to failed cytokinesis. This results in cells with multiple nuclei and an abnormal number of chromosomes, a condition known as genomic instability that is a hallmark of many cancers. Altered septin expression has been linked to several tumor types and is thought to promote tumor growth.

In the nervous system, septins are implicated in neurodegenerative diseases. In conditions like Alzheimer’s disease, specific septins have been found within the characteristic protein aggregates known as neurofibrillary tangles. Similarly, in Parkinson’s disease, a septin is found co-localized with α-synuclein, the primary component of Lewy bodies. This suggests that malfunctioning septins contribute to the protein misfolding that underlies these conditions.

The cellular defense system also utilizes septins to combat infections. When pathogenic bacteria invade a host cell, the cell can entrap them within cage-like structures made of septin filaments. This caging process immobilizes the bacteria and marks them for destruction through a process called autophagy. Some pathogens have evolved mechanisms to evade this septin response.