HECTD1‐Mediated Ubiquitination and Degradation of Rubicon Regulates Autophagy and Osteoarthritis Pathogenesis

Abstract

Objective Osteoarthritis (OA) is one of the most common degenerative joint diseases and is associated with autophagy suppression. However, the molecular mechanism of autophagy regulation in the context of OA is not fully understood. In this study, we sought to determine the role that HECTD1 plays in the pathogenesis of OA. Methods We used RNA sequencing analysis to explore the differential expression of E3 ubiquitin ligase genes in healthy human cartilage and human cartilage affected by OA. Using surgery‐ and aging‐induced OA mouse models, we comprehensively analyzed the function of the screened gene Hectd1 in the development of OA; furthermore, we dissected the mechanism by which HECTD1 regulates autophagy and OA progression using a combination of molecular biologic, cell biologic, and biochemical approaches. Results HECTD1 was significantly down‐regulated in human OA cartilage samples compared to healthy cartilage samples. Overexpression of HECTD1 in mouse joints alleviated OA pathogenesis, whereas conditional depletion of Hectd1 in cartilage samples aggravated surgery‐ and aging‐induced OA pathogenesis. Mechanistically, HECTD1 bound to Rubicon and ubiquitinated Rubicon at lysine residue 534, which targets Rubicon for proteasomal degradation. More importantly, HECTD1‐mediated Rubicon degradation regulated chondrocyte autophagy, leading to mitigation of stress‐induced chondrocyte death and the subsequent progression of OA. Conclusion HECTD1 plays a crucial role in the pathogenesis of OA, in that HECTD1 regulates chondrocyte autophagy by ubiquitinating and targeting Rubicon for proteasomal degradation.

Identification and functional analysis of rare HECTD1 missense variants in human neural tube defects

“…HECTD1 could broadly influences development by regulating the STRIPAK complex, chromatin remodeling, cholesterol export, and protein translation (Aleidi et al 2015 , 2018 ; Beard et al 2016 ; Lampersberger et al 2023 ; Li et al 2015 ; Lu et al 2022 ; Lv et al 2021 ). HECTD1 influences proliferation, apoptosis, autophagy, DNA damage repair, and mitochondrial function (Beard et al 2016 ; Bennett et al 2020 ; Duhamel et al 2018 ; Liao et al 2023 ; Lu et al 2022 ; Salas et al 2023 ; Segref et al 2014 ; Uemoto et al 2022 ; Vaughan et al 2022 ). Intriguingly, the Chinese NTD cohort utilized in this study was collected in a region where folate deficiency is well documented (Liu et al 2016 ; Meng et al 2015 ).…”

Identification and Functional Analysis of Rare HECTD1 Missense Variants in Human Neural Tube Defects

“…HECTD1 could broadly influence development by regulating the STRIPAK complex, chromatin remodeling, cholesterol export, and protein translation ( Aleidi et al 2015 ; Aleidi et al 2018 ; Beard et al 2016 ; Lampersberger et al 2023 ; Li et al 2015 ; Lu et al 2022 ; Lv et al 2021 ). HECTD1 influences proliferation, apoptosis, autophagy, DNA damage repair, and mitochondrial function ( Beard et al 2016 ; Bennett et al 2020 ; Duhamel et al 2018 ; Liao et al 2023 ; Lu et al 2022 ; Segref et al 2014 ; Uemoto et al 2022 ; Vaughan et al 2022 ). HECTD1 is also involved in inflammation in astrocytes, microglia, and other cell types ( Li et al 2020 ; Liao et al 2023 ; Tang et al 2021 ; Zhang et al 2020 ) and can regulate synaptic function by regulating the expression of glutamate transporter 1 (GLT-1) in astrocytes ( Zeng et al 2022 ).…”

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

“…The E3 ubiquitin ligase HECTD1 (HECT domain E3 ubiquitin protein ligase 1) has been proposed to control autophagy and osteoarthritis pathogenesis via degradation of Rubicon (48). The expression of HECTD1 was remarkably reduced in patients with osteoarthritis compared with healthy cartilage tissues.…”

“…Consistently, upregulation of HECTD1 alleviated pathogenesis of osteoarthritis in mouse joints. HECTD1 can interact with Rubicon at K534 and cause ubiquitination and proteasomal degradation of Rubicon, contributing to attenuation of stress-mediated chondrocyte death and osteoarthritis progression (48). Casitas B-lineage lymphoma b (Cbl-b) E3 ubiquitin ligase has been demonstrated to regulate cancer immunotherapy (93).…”