CD98 heavy chain (CD98hc), also known as Solute Carrier Family 3 Member 2 (SLC3A2), is a fundamental component of cellular machinery found across all human tissues. This highly conserved protein functions as an anchor, necessary for the cell’s ability to acquire essential nutrients. Located on the cell surface, CD98hc helps maintain cellular homeostasis. Its influence connects metabolic needs directly to processes like cell growth and immune response.
What is CD98hc?
CD98hc is classified as SLC3A2, a gene encoding a Type II transmembrane glycoprotein. The protein spans the cell membrane, but its main bulk, including the heavily glycosylated extracellular domain, resides outside the cell. The human protein consists of 630 amino acid residues, featuring a short intracellular tail, a single transmembrane segment, and a large external portion.
The protein’s function hinges on its structure and its need to form a complex with other proteins. It serves as the heavy chain in a heterodimeric unit, covalently linked to a light chain partner through a disulfide bond. The extracellular domain of CD98hc acts as a chaperone, guiding the light chain to the plasma membrane. Without the heavy chain, the light chain components cannot reach the cell surface to become functional transporters.
Amino Acid Transport Regulation
The primary function of CD98hc is regulating the transport of amino acids across the cell membrane. CD98hc does not transport molecules itself but acts as a structural subunit for a family of light chain proteins that execute the movement of amino acids. These light chains belong to the SLC7 family of amino acid permeases, including transporters like LAT1, LAT2, and xCT.
When CD98hc pairs with a light chain, it forms a functional heterodimeric transporter, such as the LAT1-CD98hc complex. This complex facilitates the uptake of large, neutral amino acids, including branched-chain amino acids (BCAAs) like leucine, isoleucine, and valine, as well as phenylalanine and tryptophan. The transport mechanism is typically an obligatory antiporter, mediating the exchange of two amino acids across the membrane in opposite directions.
The uptake of specific amino acids, particularly leucine, is important because it acts as a signaling molecule. Once inside the cell, leucine helps activate the mechanistic Target of Rapamycin (mTOR) pathway, a regulator of cell growth, proliferation, and protein synthesis. By controlling the availability of these amino acids, CD98hc indirectly regulates the cell’s metabolic state and growth rate. This transport directly links the cell’s nutritional status to its decision to grow and divide.
Beyond Transport: Immune System and Cell Proliferation
CD98hc has functions independent of its transport partners, particularly in cell signaling and adhesion. The heavy chain interacts directly with integrins, specifically the \(\beta_1\) and \(\beta_3\) subunits, to amplify their downstream signaling. This interaction modulates cellular behaviors such as cell spreading, migration, and resistance to programmed cell death (apoptosis).
This non-transport function is relevant in the immune system, where CD98hc was originally identified as a lymphocyte activation antigen. Upon T-cell activation, CD98hc expression increases significantly, becoming required for the rapid clonal expansion of T and B lymphocytes. Studies show that the integrin-binding domain of CD98hc, rather than its transport function, is the necessary component for this rapid proliferation in B cells.
CD98hc promotes adaptive immunity by supporting the rapid proliferation needed for B cells to differentiate into antibody-secreting plasma cells. It also contributes to T-cell-mediated responses and the differentiation of T-helper 1 (Th1) cells, which are required to mount an effective immune response. CD98hc acts as a switch, enabling the high-demand growth and signaling necessary for an active and adaptive immune response.
CD98hc in Disease and Therapeutic Targeting
Dysfunction in CD98hc or its associated light chains is implicated in several human diseases, from inherited metabolic disorders to complex diseases like cancer. For example, a genetic defect in the b\(^{0,+}\)AT light chain causes Cystinuria, a condition characterized by impaired transport of dibasic amino acids in the kidney. This failure in reabsorption leads to the accumulation of cystine and the formation of kidney stones.
CD98hc is frequently overexpressed in numerous malignancies, including breast, prostate, colon, and head and neck squamous cell carcinomas. This high expression provides cancer cells with a competitive advantage by increasing nutrient uptake necessary to sustain rapid, uncontrolled growth. The protein’s dual role in nutrient uptake and integrin signaling promotes tumor growth, metastasis, and resistance to therapies like chemotherapy and radiation.
Due to its broad involvement in cellular growth and surface location, CD98hc is an attractive target for therapeutic intervention. Targeting the CD98hc-LAT1 complex in cancer cells is a strategy to starve the tumor of amino acids and inhibit the pro-growth mTOR pathway. Research is also exploring CD98hc as a delivery platform, utilizing its high expression on the blood-brain barrier to transport therapeutic molecules into the central nervous system. Furthermore, blocking CD98hc function in immune cells is being investigated to treat autoimmune diseases like multiple sclerosis by suppressing pathological clonal expansion.