Macropinocytosis is a fundamental process by which cells take in substances from their external environment. This cellular mechanism allows for the bulk uptake of extracellular fluid and dissolved molecules. It is involved in various normal cellular functions and, at times, plays a role in disease progression.
Defining Macropinocytosis
Macropinocytosis is a form of endocytosis, a general process where cells internalize external materials by engulfing them with their cell membrane. It is distinguished by its non-selective nature, taking in large volumes of extracellular fluid and dissolved substances without requiring specific receptors. This process is driven by dynamic changes in the cell’s membrane, specifically through “membrane ruffling,” rather than specific binding events.
Other endocytic pathways operate differently. Clathrin-mediated endocytosis involves specific protein coats that form small vesicles to internalize particular receptors. Caveolae-mediated endocytosis uses flask-shaped indentations to internalize specific molecules in smaller vesicles. Phagocytosis, often called “cell eating,” involves the engulfment of large particles, such as bacteria or cellular debris, by specialized cells, which is a more targeted process. Macropinocytosis results in larger vesicles, known as macropinosomes, typically ranging from 0.2 to 5 micrometers in diameter, and its formation is highly dependent on the cell’s internal actin framework.
The Process of Macropinocytosis
The formation of macropinosomes begins with the dynamic reorganization of the cell’s outer membrane, leading to membrane ruffling. These ruffles are actin-rich protrusions that extend outwards from the cell surface. These extensions can take various forms, including planar lamellipodia, circular ruffles, or blebs, depending on the cell type and external signals.
As these membrane ruffles extend, they can fold back onto themselves, creating a cup-shaped structure that traps extracellular fluid. Alternatively, multiple ruffles can coalesce and seal off, forming a large, irregular vesicle called a macropinosome. This engulfment process is heavily reliant on the actin cytoskeleton, which provides the mechanical force for membrane movement and the subsequent sealing of the macropinosome.
Once formed, the macropinosome is internalized and undergoes a series of maturation steps. These large vesicles typically acidify and can fuse with other cellular compartments, such as early endosomes and lysosomes. This fusion allows for the breakdown of the macropinosome’s contents, releasing nutrients or other molecules into the cell, and also allows for the recycling of membrane components back to the cell surface.
Macropinocytosis in Healthy Cells
In healthy cells, macropinocytosis plays diverse physiological roles. One significant function is nutrient scavenging, especially in environments where nutrients are scarce. Cells use macropinocytosis to take up extracellular proteins and other macromolecules from the surrounding fluid, which are then broken down into smaller components like amino acids to support cell growth and metabolism.
Macropinocytosis also has a role in the immune system, particularly in dendritic cells and macrophages. These immune cells constantly sample their environment for foreign invaders or antigens. By performing macropinocytosis, they non-selectively internalize large volumes of extracellular fluid containing potential antigens. This uptake allows the immune cells to process and present these antigens to other immune cells, contributing to the body’s defense against pathogens.
Beyond nutrient uptake and immune surveillance, macropinocytosis also contributes to cell volume regulation. By internalizing fluid, cells adjust their internal volume. This mechanism helps maintain cellular homeostasis in response to changes in the extracellular environment.
Macropinocytosis and Disease
Macropinocytosis can be exploited or altered in various disease states, particularly in the context of cancer. Many cancer cells, especially those with mutations in genes like KRAS, exhibit increased macropinocytosis. This enhanced uptake allows tumor cells to scavenge extracellular proteins and other nutrients from their often nutrient-poor microenvironment, providing a sustained supply of amino acids and other building blocks for their rapid growth.
In cancer cells with oncogenic KRAS mutations, macropinocytosis is a significant pathway for acquiring extracellular proteins. This nutrient scavenging can contribute to resistance against certain cancer therapies by maintaining pathways that promote cell survival and growth. Therefore, targeting macropinocytosis is being explored as a potential strategy to limit tumor progression.
Beyond cancer, macropinocytosis can also be exploited by various pathogens to gain entry into host cells. Certain viruses, such as vaccinia virus and adenovirus, as well as some bacteria, can hijack this process for cellular internalization. Additionally, some neurodegenerative protein deposits and prions have been shown to invade new host cells through macropinocytosis, suggesting its involvement in the spread of these conditions.