TRIM21-regulated Annexin A2 plasma membrane trafficking facilitates osteosarcoma cell differentiation through the TFEB-mediated autophagy

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, which is characterized by dysfunctional autophagy and poor differentiation. Our recent studies have suggested that the tripartite motif containing-21 (TRIM21) plays a crucial role in regulating OS cell senescence and proliferation via interactions with several proteins. Yet, its implication in autophagy and differentiation in OS is largely unknown. In the present study, we first showed that TRIM21 could promote OS cell autophagy, as determined by the accumulation of LC3-II, and the degradation of cargo receptor p62. Further, we were able to identify that Annexin A2 (ANXA2), as a novel interacting partner of TRIM21, was critical for TIRM21-induced OS cell autophagy. Although TRIM21 had a negligible effect on the mRNA and protein expressions of ANXA2, we did find that TRIM21 facilitated the translocation of ANXA2 toward plasma membrane (PM) in OS cells through a manner relying on TRIM21-mediated cell autophagy. This functional link has been confirmed by observing a nice co-expression of TRIM21 and ANXA2 (at the PM) in the OS tissues. Mechanistically, we demonstrated that TRIM21, via facilitating the ANXA2 trafficking at the PM, enabled to release the transcription factor EB (TFEB, a master regulator of autophagy) from the ANXA2-TFEB complex, which in turn entered into the nucleus for the regulation of OS cell autophagy. In accord with previous findings that autophagy plays a critical role in the control of differentiation, we also demonstrated that autophagy inhibited OS cell differentiation, and that the TRIM21/ANXA2/TFEB axis is implicated in OS cell differentiation through the coordination with autophagy. Taken together, our results suggest that the TRIM21/ANXA2/TFEB axis is involved in OS cell autophagy and subsequent differentiation, indicating that targeting this signaling axis might lead to a new clue for OS treatment.

A Highly Selective GSK-3β Inhibitor CHIR99021 Promotes Osteogenesis by Activating Canonical and Autophagy-Mediated Wnt Signaling

“…Autophagy has been implicated in the differentiation of osteoblasts. It has been demonstrated that autophagy-related proteins are involved in osteoblast differentiation and bone formation, and other studies have reported that autophagy affects osteoblast mineralization and osteocyte network structure (39,40). Mouse models knocking out autophagy genes have shown a significant reduction in osteophagy volume, number, and thickness (41,42).…”

Presence and possible impact of Fcγ receptors on resident kidney cells in health and disease

“…99 TRIM21 overexpression was shown to upregulate the main autophagic marker light chain 3-II, triggering the formation of autophagosomes and their subsequent delivery to lysosomes. 100 Autophagy plays an important role in renal function, mainly by maintaining podocyte homeostasis and viability, insulin sensing and permeability of the renal filtration barrier to albumin. 101 The downregulation of autophagy with accompanying histological renal lesions was observed in patients with diabetes with proteinuria.…”

“…microtubule‐associated protein 1A/1B‐light chain 3] 99 . TRIM21 overexpression was shown to upregulate the main autophagic marker light chain 3‐II, triggering the formation of autophagosomes and their subsequent delivery to lysosomes 100 . Autophagy plays an important role in renal function, mainly by maintaining podocyte homeostasis and viability, insulin sensing and permeability of the renal filtration barrier to albumin 101 .…”

Annexin A2 plays a key role in protecting against cisplatin-induced AKI through β-catenin/TFEB pathway

“…Annexin A2 (ANXA2), a 39-kDa phospholipid-binding protein, belongs to the Annexin family [ 18 ] and plays a key role in membrane organization, traffic, and fusion [ 19 , 20 ]. With the high involvement in dynamic events of membrane events [ 21 , 22 ], ANXA2 plays a crucial role in mediating autophagy [ 23 , 24 ]. Indeed, ANXA2 ablation leads to the defects of phagophore membrane initiation [ 25 ] and the deficiency in autophagy setting [ 26 ].…”