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FAM111A induces nuclear dysfunction in disease and viral restriction
Minghua Nie1, Martina Oravcová1, Yasaman Jami-Alahmadi2
1Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
EMBO Reports
|December 28, 2020
Summary
Mutations in the nuclear protease FAM111A cause rare genetic disorders and restrict viral replication. This study reveals deregulated FAM111A activity disrupts nuclear function, unifying its roles in disease and antiviral defense.
Area of Science:
- Molecular Biology
- Virology
- Genetics
Background:
- Mutations in FAM111A cause Kenny-Caffey syndrome (KCS2) and osteocraniostenosis (OCS).
- FAM111A acts as a restriction factor against certain viruses like SV40.
- The precise functions of FAM111A in viral restriction and disease etiology are not well understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying FAM111A's roles in viral restriction and genetic disorders.
- To investigate the function of FAM111A and its mutants in cellular and viral contexts.
Main Methods:
- Analysis of FAM111A patient mutants for hyperactivity and cytotoxicity.
- Observation of nuclear structure and pore distribution changes.
- Investigation of FAM111A interaction with cellular components like nucleoporins and GANP.
Main Results:
- FAM111A patient mutants are hyperactive, cytotoxic, and induce apoptosis-like nuclear phenotypes.
- Wild-type FAM111A disrupts nuclear barrier function during viral replication.
- FAM111A-induced phenotypes occur independently of caspases and involve nucleoporins and GANP.
Conclusions:
- Deregulated FAM111A activity, due to mutations, causes KCS2 and OCS by disrupting nuclear integrity.
- FAM111A's nuclear function is crucial for restricting viral replication.
- A unified mechanism explains FAM111A's dual role in genetic disease and antiviral immunity.
Keywords:
FAM111AKenny-Caffey syndromeOsteocraniostenosisnuclear pore complexrestriction of polyomavirus replicationMore Related Videos
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