Abstract
Beta2-microglobulin (B2M) a key component of major histocompatibility complex class I molecules, which aid cytotoxic T-lymphocyte (CTL) immune response. However, the majority of studies of B2M have focused only on amyloid fibrils in pathogenesis to the neglect of its role of antimicrobial activity. Indeed, B2M also plays an important role in innate defense and does not only function as an adjuvant for CTL response. A previous study discovered that human aggregated B2M binds the surface protein structure in Streptococci, and a similar study revealed that sB2M-9, derived from native B2M, functions as an antibacterial chemokine that binds Staphylococcus aureus. An investigation of sB2M-9 exhibiting an early lymphocyte recruitment in the human respiratory epithelium with bacterial challenge may uncover previously unrecognized aspects of B2M in the body’s innate defense against Mycobactrium tuberculosis. B2M possesses antimicrobial activity that operates primarily under pH-dependent acidic conditions at which B2M and fragmented B2M may become a nucleus seed that triggers self-aggregation into distinct states, such as oligomers and amyloid fibrils. Modified B2M can act as an antimicrobial peptide (AMP) against a wide range of microbes. Specifically, these AMPs disrupt microbe membranes, a feature similar to that of amyloid fibril mediated cytotoxicity toward eukaryotes. This study investigated two similar but nonidentical effects of B2M: the physiological role of B2M, in which it potentially acts against microbes in innate defense and the role of B2M in amyloid fibrils, in which it disrupts the membrane of pathological cells. Moreover, we explored the pH-governing antibacterial activity of B2M and acidic pH mediated B2M amyloid fibrils underlying such cytotoxicity.
Highlights
Background of Beta2 MicroglobulinHuman beta-2 microglobulin (B2M), a small gene composed of four exons at chromosome 15q21.1, encodes a full-length, 119-residue protein that becomes a 99-residue matureB2M with a secondary structure of seven beta-pleated sheets
B2M is characterized as a scaffolding protein that retains the native structure of major histocompatibility complex (MHC) class I molecules in antigen present cells (APCs) to present peptides to cytotoxic CD8+ T cells [2,3,4]
In addition to being a part of nonmembrane-bound proteins associated with MHC class I molecules, B2M can be released in free form in serum
Summary
Human beta-2 microglobulin (B2M), a small gene composed of four exons at chromosome 15q21.1, encodes a full-length, 119-residue protein that becomes a 99-residue mature. B2M is characterized as a scaffolding protein that retains the native structure of MHC class I molecules in antigen present cells (APCs) to present peptides to cytotoxic CD8+ T cells [2,3,4]. Because MHC class I molecules can affect many physiological functions in mice and human beings, animal models of an engineered B2M deficiency with low MHC class I levels address major challenges in the endogenous cross-presentation of the host [5,6,7]. In addition to being a part of nonmembrane-bound proteins associated with MHC class I molecules, B2M can be released in free form in serum. B2M with a predominantly beta-pleated sheet can form molecular aggregation associated with dialysis-related amyloidosis (DRA) [10,11], a feature of the deposition of amyloid fibrils in the skeletal muscular system. B2M shedding, either intact, fragmented or in the form of amyloid fibrils, may be disastrous for the host or their generation represents an alternative defense against diseases, which is discussed as below
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