Ig light chains are secreted predominantly as monomers

Area of Science:

• Immunology
• Molecular Biology
• Protein Biochemistry

Background:

• Immunoglobulin (Ig) light (L) chains are secreted as part of antibodies and also as free chains.
• Free L chain secretion is implicated in various disease pathologies.
• The secretion of free L chains differs from other free subunits, which are typically retained intracellularly.

Purpose of the Study:

• To investigate the role of dimerization in the secretion of free immunoglobulin light chains.
• To determine if light chain dimerization is a prerequisite for secretion.
• To elucidate the association state of free light chains in different cellular contexts.

Main Methods:

• Coexpression of wild-type and mutant L chains with altered secretory phenotypes.
• Nonreducing gel electrophoresis to detect disulfide-bonded dimers.
• Chemical cross-linking and density gradient centrifugation to assess noncovalent dimers.
• Detection of heterodimers using a heavy-light chain chimera.

Main Results:

• Mutant L chains with altered secretory phenotypes were retained intracellularly, behaving independently of wild-type chains.
• A negligible fraction of free kappa or lambda light chains exists as disulfide-bonded dimers.
• No significant pool of noncovalent light chain dimers was detected.
• Noncovalent heterodimers were readily detected, confirming the sensitivity of detection methods for L chain dimers.

Conclusions:

• Light chain dimerization is a rare event.
• Dimerization does not facilitate or is not required for the secretion of free immunoglobulin light chains.
• These findings hold true across different host cells, including myeloma cells and COS fibroblasts.