CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development.

Area of Science:

• Molecular Biology
• Developmental Biology
• Biochemistry

Background:

• Ubiquitin-like protein (UBL) conjugation regulates diverse biological processes.
• The UFM1 system is a novel UBL conjugation pathway involved in mouse development, but its functions are not fully understood.
• CDK5RAP3 is a potential ufmylation substrate crucial for zebrafish development.

Purpose of the Study:

• To investigate the role of CDK5RAP3 in mammalian liver development and function.
• To elucidate the mechanism by which CDK5RAP3 influences ufmylation.
• To explore the broader implications of ufmylation in mammalian development.

Main Methods:

• Generation and analysis of Cdk5rap3 knockout mice (full and hepatocyte-specific).
• Assessment of liver development, hepatic functions (glucose and lipid metabolism), and endoplasmic reticulum stress.
• Investigation of CDK5RAP3 interaction with UFL1 and its effect on the cellular ufmylation profile.

Main Results:

• Cdk5rap3 knockout mice exhibited prenatal lethality with severe liver hypoplasia, delayed proliferation, and impaired differentiation.
• Hepatocyte-specific knockout mice showed post-weaning lethality due to hypoglycemia and disrupted lipid metabolism.
• CDK5RAP3 depletion induced endoplasmic reticulum stress and activated unfolded protein responses, interacting with UFL1 and altering ufmylation patterns.

Conclusions:

• CDK5RAP3 plays a critical role in liver development and hepatic functions.
• CDK5RAP3 acts as a substrate adaptor for the UFM1 E3 ligase UFL1, highlighting its importance in the ufmylation pathway.
• This study suggests a significant involvement of ufmylation in mammalian development and liver homeostasis.