Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

Abstract

In inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

The Degradation of Hyaluronan in the Skin

“…Alternatively, CEMIP may function as an adaptor molecule for an unknown hyaluronidase via which it assists in the internalization of intermediate-sized HA into the cell. A further explanation suggests that CEMIP induces the degradation of HA when bound to the ANXA1 protein [ 50 ]. Interestingly, a recent report by Dokoshi et al indicated that CEMIP is the major inducible gene responsible for HA catabolism in mice.…”

Hyaluronan: A key player or just a bystander in skin photoaging?

“…Cell migration‐inducing and hyaluronan‐binding protein (CEMIP, also known as KIAA1199 and HYBID) specifically binds HA and mediates the depolymerization of HA via the cell membrane‐associated clathrin‐coated pit endocytic pathway. In addition, a recent report suggested that CEMIP may increase HA degradation when associated with ANXA‐1 on cellular membranes 62 . CEMIP is localized on the cytoplasmic membrane and in the cytoplasm.…”

“…In addition, a recent report suggested that CEMIP may increase HA degradation when associated with ANXA-1 on cellular membranes. 62 CEMIP is localized on the cytoplasmic membrane and in the cytoplasm.…”

The role of hyaluronan synthesis and degradation in the critical respiratory illness COVID-19

“…In recent years, HA degrading proteins structurally different from the HYAL family have been identified. The cell migration inducing protein (CEMIP), also known as KIAA1199, and the transmembrane protein 2 (Tmem2) both have been shown to contribute to extracellular degradation of HA in fibroblasts ( 31 – 34 ). Therefore, the regulation of HA synthesis and degradation regulates to the bioavailability of different HA forms with discrete biological properties.…”

“…The degradation of HMW-HA into smaller fragments starts by the activities of Hyal-2, TMEM2, CEMIP, and reactive oxygen species (ROS) at cell surfaces ( 16 ). The smaller LMW-HA fragments may then be bound and cleared by AMs with further intracellular degradation mediated by Hyal-1 (and possibly CEMIP) and by the activity of exoglycosidases (β-glucuronidase and β-N-acetylhexosaminidase) ( 31 – 34 , 55 ). The LMW-HA fragments are bioactive polymers with a polydisperse molecular weight distribution in the range of ∼10 4 –10 5 Da ( 56 ).…”