Thyroglobulin Interactome Profiling Defines Altered Proteostasis Topology Associated With Thyroid Dyshormonogenesis

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Thyroglobulin (Tg) is essential for thyroid hormone synthesis (thyroxine and triiodothyronine).
• Mutations in the Tg gene lead to congenital hypothyroidism due to defective Tg secretion.
• The secretory proteostasis network, involving chaperones and degradation factors, regulates Tg processing and secretion.

Purpose of the Study:

• To define the thyroglobulin (Tg) proteostasis interactome.
• To understand how Tg gene mutations associated with congenital hypothyroidism alter protein processing and secretion.
• To identify potential therapeutic targets for restoring thyroid hormone biosynthesis.

Main Methods:

• Utilized multiplexed quantitative affinity purification-mass spectrometry.
• Analyzed the Tg proteostasis interactome for wild-type (WT) Tg and congenital hypothyroidism variants.
• Investigated changes in protein interactions and quality control pathways.

Main Results:

• Identified common proteostasis network imbalances in mutant Tg processing, including increased chaperoning and endoplasmic reticulum-associated degradation (ERAD).
• Revealed mutation-specific alterations in N-glycosylation and oligosaccharyltransferase complex interactions for degradation.
• Demonstrated distinct proteostasis requirements for different Tg variants.

Conclusions:

• Mutant Tg processing involves widespread proteostasis network dysregulation.
• Targeting specific proteostasis components and pathways offers a potential therapeutic strategy.
• Restoring Tg secretion and thyroid hormone biosynthesis may be achievable by modulating these pathways.