Extracellular, circulating proteasomes and ubiquitin — Incidence and relevance

Abstract

The ubiquitin-proteasome system is the major pathway for intracellular protein degradation and is also deeply involved in the regulation of most basic cellular processes. Its proteolytic core, the 20S proteasome, has found to be attached also to the cell plasma membrane and certain observations are interpreted as to suggest that they may be released into the extracellular medium, e.g. in the alveolar lining fluid, epididymal fluid and possibly during the acrosome reaction. Proteasomes have also been detected in normal human blood plasma and designated circulating proteasomes; these have a comparatively low specific activity, a distinct pattern of subtypes and their exact origin is still enigmatic. In patients suffering from autoimmune diseases, malignant myeloproliferative syndromes, multiple myeloma, acute and chronic lymphatic leukaemia, solid tumour, sepsis or trauma, respectively, the concentration of circulating proteasomes has been found to be elevated, to correlate with the disease state and has even prognostic significance. Similarly, ubiquitin has been discovered as a normal component of human blood and seminal plasma and in ovarian follicular fluid. Increased concentrations were measured in diverse pathological situations, not only in blood plasma but also in cerebrospinal fluid, where it may have neuroprotective effects. As defective spermatozoa are covered with ubiquitin in the epididymal fluid, extracellular ubiquitination is proposed to be a mechanism for quality control in spermatogenesis. Growing evidence exists also for a participation of extracellular proteasomes and ubiquitin in the fertilization process.

Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier

“…An increase of extracellular proteasomes has been noted in other inflammatory and infectious conditions before, and it is unclear whether they are released by cells that are damaged or dead as a result of these conditions or are actively excreted as a defense mechanism to help clear the conditions. 34 There is some evidence for both hypotheses. For example, inflammation attracts antigen-presenting cells that use (immuno)proteasomes for the breakdown of proteins for presentation in the major histocompatibility complex -I, 35 whereas in vitro studies have shown that T cells excrete proteasomes using exosomes and that this excretion is enhanced when T cells are activated.…”

Proteasomal Regulation of Pulmonary Fibrosis

“…Proteasome proteins were detected by mass spectrometry and Western blotting in bronchoalveolar lavage fluid (BALF) of eight healthy subjects undergoing elective surgery. All three proteasome activities were identified, and BAL supernatant successfully cleaved albumin in an ATP-and ubiquitin-independent manner (40). In a subsequent study, BALF from patients with ARDS was found to have increased proteasomal proteins compared with BALF from control subjects, but proteasomal activity was significantly decreased compared with healthy control subjects.…”

Protein Interaction between Ameloblastin and Proteasome Subunit α Type 3 Can Facilitate Redistribution of Ameloblastin Domains within Forming Enamel

“…The proteasome is widely acknowledged to localize in the nucleus and cytoplasm in eukaryotes (68). However, several recent investigations reported that a biologically active proteasome core is present in extracellular space, including the alveolar space (69,70), blood plasma (71), and cerebrospinal fluid (72). These data suggest that cells secrete/shed proteasome and/or proteasome subunits into the extracellular space, wherein the proteasome components may retain function.…”