ANKLE2

Last update 08 May 2025

Basic Info

Synonyms

ANKLE2, ankyrin repeat and LEM domain containing 2, Ankyrin repeat and LEM domain-containing protein 2

+ [4]

Introduction

Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit (PubMed:22770216). Coordinates the control of BAF/BANF1 dephosphorylation by inhibiting VRK1 kinase and promoting dephosphorylation of BAF/BANF1 by protein phosphatase 2A (PP2A), thereby facilitating nuclear envelope assembly (PubMed:22770216). May regulate nuclear localization of VRK1 in non-dividing cells (PubMed:31735666). It is unclear whether it acts as a real PP2A regulatory subunit or whether it is involved in recruitment of the PP2A complex (PubMed:22770216). Involved in brain development (PubMed:25259927).

100 Clinical Results associated with ANKLE2

100 Translational Medicine associated with ANKLE2

0 Patents (Medical) associated with ANKLE2

Literatures (Medical) associated with ANKLE2

05 Feb 2025·mBio

Microcephaly protein ANKLE2 promotes Zika virus replication

Article

Author: Adia, Neil A. B. ; Hoang, Vivian ; Prince, Brian ; Rückert, Claudia ; Shah, Priya S. ; Evans, Matthew J. ; Beesabathuni, Nitin Sai ; Klaessens, Thomas N. ; Cherkashchenko, Liubov ; Florio, Cole J. ; Fishburn, Adam T. ; Lopez, Nicholas J. ; Haggard Arcé, Sophia T. ; Richardson, R. Blake ; Becker, Sydney S. ; Shiu, Traci N.

ABSTRACT Orthoflaviviruses are positive-sense single-stranded RNA viruses that hijack host proteins to promote their own replication. Zika virus (ZIKV) is infamous among orthoflaviviruses for its association with severe congenital birth defects, notably microcephaly. We previously mapped ZIKV-host protein interactions and identified the interaction between ZIKV non-structural protein 4A (NS4A) and host microcephaly protein ankyrin repeat and LEM domain-containing 2 (ANKLE2). Using a fruit fly model, we showed that NS4A induced microcephaly in an ANKLE2-dependent manner. Here, we explore the role of ANKLE2 in ZIKV replication to understand the biological significance of the interaction from a viral perspective. We observe that ANKLE2 localization is drastically shifted to sites of NS4A accumulation during infection and that knockout of ANKLE2 reduces ZIKV replication in multiple human cell lines. This decrease in virus replication is coupled with a moderate increase in innate immune activation. Using microscopy, we observe dysregulated formation of virus-induced endoplasmic reticulum rearrangements in ANKLE2 knockout cells. Knockdown of the ANKLE2 ortholog in Aedes aegypti cells also decreases virus replication, suggesting ANKLE2 is a beneficial replication factor across hosts. Finally, we show that NS4A from four other orthoflaviviruses physically interacts with ANKLE2 and is also beneficial to their replication. Thus, ANKLE2 likely promotes orthoflavivirus replication by regulating membrane rearrangements that serve to accelerate viral genome replication and protect viral dsRNA from immune detection. Taken together with our previous results, our findings indicate that ZIKV and other orthoflaviviruses hijack ANKLE2 for a conserved role in replication, and this drives unique pathogenesis for ZIKV since ANKLE2 has essential roles in developing tissues. IMPORTANCEZIKV is a major concern due to its association with birth defects, including microcephaly. We previously identified a physical interaction between ZIKV NS4A and host microcephaly protein ANKLE2. Mutations in ANKLE2 cause congenital microcephaly, and NS4A induces microcephaly in an ANKLE2-dependent manner. Here, we establish the role of ANKLE2 in ZIKV replication. Depletion of ANKLE2 from cells significantly reduces ZIKV replication and disrupts virus-induced membrane rearrangements. ANKLE2’s ability to promote ZIKV replication is conserved in mosquito cells and for other related mosquito-borne orthoflaviviruses. Our data point to an overall model in which ANKLE2 regulates virus-induced membrane rearrangements to accelerate orthoflavivirus replication and avoid immune detection. However, ANKLE2’s unique role in ZIKV NS4A-induced microcephaly is a consequence of ZIKV infection of important developing tissues in which ANKLE2 has essential roles.

01 Apr 2024·Disease Models & Mechanisms

Molecular functions of ANKLE2 and its implications in human disease

Review

Author: Florio, Cole J. ; Link, Nichole L. ; Lopez, Nick J. ; Fishburn, Adam T. ; Shah, Priya S.

ABSTRACTAnkyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.

01 Jan 2023·Life Science Alliance

CRISPRi screening reveals regulators of tau pathology shared between exosomal and vesicle-free tau

Article

Author: Balistreri, Giuseppe ; van Roijen, Marloes ; Fernandes, Avinash ; Götz, Jürgen ; Hand, Gabriel Rhys ; Briner, Adam ; Polanco, Juan Carlos ; Akimov, Yevhen

The aggregation of the microtubule-associated protein tau is a defining feature of Alzheimer’s disease and other tauopathies. Tau pathology is believed to be driven by free tau aggregates and tau carried within exosome-like extracellular vesicles, both of which propagate trans-synaptically and induce tau pathology in recipient neurons by a corrupting process of seeding. Here, we performed a genome-wide CRISPRi screen in tau biosensor cells and identified cellular regulators shared by both mechanisms of tau seeding. We identified ANKLE2, BANF1, NUSAP1, EIF1AD, and VPS18 as the top validated regulators that restrict tau aggregation initiated by both exosomal and vesicle-free tau seeds. None of our validated hits affected the uptake of either form of tau seeds, supporting the notion that they operate through a cell-autonomous mechanism downstream of the seed uptake. Lastly, validation studies with human brain tissue also revealed that several of the identified protein hits are down-regulated in the brains of Alzheimer’s patients, suggesting that their decreased activity may be required for the emergence or progression of tau pathology in the human brain.

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ANKLE2

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