Proteasomien

Proteasomes are multisubunit protease complexes that degrade most intracellular proteins tagged with ubiquitin, a central process in cellular protein homeostasis. By removing damaged, misfolded, or regulatory proteins, they influence cell cycle progression, signaling pathways, and stress responses.

The core particle, or 20S proteasome, is a cylindrical structure formed by four stacked rings: two outer α rings and two inner β rings. The proteolytic activity resides in the β subunits (β1, β2, β5), which provide caspase-like, trypsin-like, and chymotrypsin-like specificities. Access to the catalytic chamber is gated by the α rings and can be opened by regulatory particles.

Most cellular proteolysis uses the 26S proteasome, a complex in which the 20S core is capped at one or both ends by 19S regulatory particles. The 19S particle recognizes polyubiquitinated substrates, removes ubiquitin tags via deubiquitinases, unfolds the substrate, and translocates it into the core in an ATP-dependent process for degradation.

Immunoproteasomes are specialized proteasomes formed when immune cells express alternative catalytic subunits (β1i/LMP2, β2i/MECL-1, β5i/LMP7) that replace their constitutive counterparts. This substitution alters peptide generation for major histocompatibility complex (MHC) class I antigen presentation and modulates immune responses. Additional proteasome forms, such as thymoproteasomes, contribute to specialized tissues.

Clinically, impaired or dysregulated proteasome activity is linked to cancer, neurodegenerative diseases, and aging. Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib are used to treat multiple myeloma and certain lymphomas by disrupting protein turnover, leading to proteotoxic stress in malignant cells. Side effects and resistance are important areas of ongoing research.