The Hippo terminal effector YAP boosts enterovirus replication in type 1 diabetes

Area of Science:

• Virology
• Immunology
• Endocrinology

Background:

• Enteroviral infections, especially coxsackieviruses B (CVB), are linked to type 1 diabetes (T1D) risk.
• The specific cellular host factors driving virus-induced islet autoimmunity are not fully understood.

Purpose of the Study:

• To investigate the role of the Hippo pathway effector Yes-associated Protein (YAP) in enterovirus-induced pancreatic islet autoimmunity.
• To explore YAP as a potential therapeutic target for T1D.

Main Methods:

• Analysis of YAP and CTGF expression in pancreatic tissues from T1D and autoantibody-positive donors.
• Assessing the impact of YAP modulation on CVB replication and pancreatic cell function in vitro and in vivo.
• Investigating the mechanistic interplay between YAP, TEAD, MST1, and CVB infection.

Main Results:

• YAP and its target CTGF are upregulated in the pancreas of T1D and at-risk individuals, correlating with CVB RNA presence.
• YAP overexpression enhances CVB replication, islet inflammation, and beta-cell apoptosis; YAP inhibition halts viral replication.
• YAP promotes CVB amplification and beta-cell dysfunction via a negative feedback loop involving MST1.

Conclusions:

• YAP is a critical host factor that amplifies enteroviral infections in the pancreas.
• YAP's role in promoting viral replication and beta-cell damage suggests it as a potential antiviral target for T1D prevention and treatment.