AZI2

Last update 08 May 2025

Basic Info

Synonyms

5-azacytidine induced 2, 5-azacytidine-induced protein 2, AZ2

+ [7]

Introduction

Adapter protein which binds TBK1 and IKBKE playing a role in antiviral innate immunity (PubMed:14560022, PubMed:21931631). Activates serine/threonine-protein kinase TBK1 and facilitates its oligomerization (PubMed:14560022, PubMed:21931631). Enhances the phosphorylation of NF-kappa-B p65 subunit RELA by TBK1 (PubMed:14560022, PubMed:21931631). Promotes TBK1-induced as well as TNF-alpha or PMA-induced activation of NF-kappa-B (PubMed:14560022, PubMed:21931631). Participates in IFNB promoter activation via TICAM1 (PubMed:15611223).

100 Clinical Results associated with AZI2

100 Translational Medicine associated with AZI2

0 Patents (Medical) associated with AZI2

Literatures (Medical) associated with AZI2

01 Oct 2024·Journal of Biological Chemistry

TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy

Article

Author: Kojima, Waka ; Kinefuchi, Hiroki ; Yamano, Koji ; Kikuchi, Reika ; Endo, Ryu ; Matsuda, Noriyuki ; Sawada, Momoha

Damaged mitochondria are selectively eliminated in a process called mitophagy. PINK1 and Parkin amplify ubiquitin signals on damaged mitochondria, which are then recognized by autophagy adaptors to induce local autophagosome formation. NDP52 and OPTN, two essential mitophagy adaptors, facilitate de novo synthesis of pre-autophagosomal membranes near damaged mitochondria by linking ubiquitinated mitochondria and ATG8 family proteins and by recruiting core autophagy initiation components. The multifunctional serine/threonine kinase TBK1 also plays an important role in mitophagy. OPTN directly binds TBK1 to form a positive feedback loop for isolation membrane expansion. TBK1 is also thought to indirectly interact with NDP52; however, its role in NDP52-driven mitophagy remains largely unknown. Here, we focused on two TBK1 adaptors, AZI2/NAP1 and TBKBP1/SINTBAD, that are thought to mediate the TBK1-NDP52 interaction. We found that both AZI2 and TBKBP1 are recruited to damaged mitochondria during Parkin-mediated mitophagy. Further, a series of AZI2 and TBKBP1 knockout constructs combined with an OPTN knockout showed that AZI2, but not TBKBP1, impacts NDP52-driven mitophagy. In addition, we found that AZI2 at S318 is phosphorylated during mitophagy, the impairment of which slightly inhibits mitochondrial degradation. These results suggest that AZI2, in concert with TBK1, plays an important role in NDP52-driven mitophagy.

01 Sep 2024·Autophagy

CALCOCO2/NDP52 associates with RAB9 to initiate an antiviral response to hepatitis B virus infection through a lysosomal degradation pathway

Article

Author: Cui, Shuzhi ; Wei, Yu ; Faure, Mathias

CALCOCO2/NDP52 recognizes LGALS8 (galectin 8)-coated invading bacteria and initiates anti-bacterial autophagy by recruiting RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1. Whether CALCOCO2 exerts similar functions against viral infection is unknown. In our recent study we show that CALCOCO2 targets envelope proteins of hepatitis B virus (HBV) to the lysosome for degradation, resulting in inhibition of viral replication. In contrast to anti-bacterial autophagy, lysosomal degradation of HBV does not require either LGALS8 or ATG5, and CALCOCO2 mutants abolishing the formation of the RB1CC1-CALCOCO2-TBKBP1-AZI2 complex maintain their inhibitory function on the virus. CALCOCO2-mediated inhibition depends on RAB9, which is a key factor in the alternative autophagy pathway. CALCOCO2 forms a complex with RAB9 only in the presence of viral envelope proteins and links HBV to the RAB9-dependent lysosomal degradation pathway. These findings reveal a new mechanism by which CALCOCO2 triggers antiviral responses against HBV infection and suggest direct roles for autophagy receptors in other lysosomal degradation pathways than canonical autophagy.

03 Mar 2024·Autophagy

AZI2 mediates TBK1 activation at unresolved selective autophagy cargo receptor complexes with implications for CD8 T-cell infiltration in breast cancer

Article

Author: Hao, Mingang ; Guan, Jun-Lin ; Yeo, Syn Kok ; Haas, Michael ; Manupati, Kanakaraju ; Yang, Fuchun ; Chen, Song

Most breast cancers do not respond to immune checkpoint inhibitors and there is an urgent need to identify novel sensitization strategies. Herein, we uncovered that activation of the TBK-IFN pathway that is mediated by the TBK1 adapter protein AZI2 is a potent strategy for this purpose. Our initial observations showed that RB1CC1 depletion leads to accumulation of AZI2, in puncta along with selective macroautophagy/autophagy cargo receptors, which are both required for TBK1 activation. Specifically, disrupting the selective autophagy function of RB1CC1 was sufficient to sustain AZI2 puncta accumulation and TBK1 activation. AZI2 then mediates downstream activation of DDX3X, increasing its interaction with IRF3 for transcription of pro-inflammatory chemokines. Consequently, we performed a screen to identify inhibitors that can induce the AZI2-TBK1 pathway, and this revealed Lys05 as a pharmacological agent that induced pro-inflammatory chemokine expression and CD8⁺ T cell infiltration into tumors. Overall, we have identified a distinct AZI2-TBK1-IFN signaling pathway that is responsive to selective autophagy blockade and can be activated to make breast cancers more immunogenic.Abbreviations: AZI2/NAP1: 5-azacytidine induced 2; CALCOCO2: calcium binding and coiled-coil domain 2; DDX3X: DEAD-box helicase 3 X-linked; FCCP: carbonyl cyanide p-triflouromethoxyphenylhydrazone; a protonophore that depolarizes the mitochondrial inner membrane; ICI: immune checkpoint inhibitor; IFN: interferon; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1.

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AZI2

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