# Uncovering the Mechanisms of Amylopectinosis in LUBAC Deficiency > **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $410,000 ## Abstract PI: Mitra, Sharmistha Glycogen is the largest soluble macromolecule in the cell and serves as a critical energy store in tissues. Co- ordinated actions by multiple enzymes control regular branching, radial spherical growth of the molecule ensuring the solubility, which is critical for tissue homeostasis. Regulatory enzymes of the glycogenesis process includes at least three E3 ubiquitin ligases, dedicated to securing glycogen’s spherical architecture. Absence of any of them leads to a glycogen structure akin to the insoluble starch amylopectin (now called polyglucosans). This process of forming polyglucosans is called amylopectinosis. Polyglucosans tend to aggregate producing insoluble deposits called polyglucosan bodies (PB). At the tissue level, precipitated PBs lead to untreatable pathologies such as fatal cardiomyopathy (in heart), disabling skeletal-myopathy (muscle), motor neuron loss (central nervous system) and neurodegeneration (brain). How deficiencies of each of these ubiquitin ligases (or their interacting proteins) and through what substrates and pathways, result in the derangement of glycogen structure is not known. In the current proposal, the PI proposes to work with Linear Ubiquitin Chain Assembly Complex (LUBAC) to identify its role in glycogen solubility control. LUBAC is a multi- protein complex composed of two E3 ubiquitin ligases – RBCK1, HOIP and an adaptor protein SHARPIN. LUBAC-deficient patients exhibit PBs in different organs, especially skeletal and cardiac muscle resulting in myopathy and cardiomyopathy with heart failure. This emphasizes LUBAC’s important role in glycogen metabolism. To date, glycogen metabolism related LUBAC substrate(s) and associated molecular mechanisms are not known. Utilizing newly created mouse models, cell lines and novel approaches, the proposed work tests the central hypothesis that LUBAC downregulates the activity of glycogen synthase (GS) and ubiquitinates longer less-branched glycogen chains to keep the glycogen soluble. Aim 1 of the research uses two newly created mouse models of LUBAC deficiency to understand Rbck1’s glycogen association. Furthermore, to understand the mechanisms of amylopectinosis, the PI investigates the influence of glycogen phosphate, and muscle/brain cell specificity for PB accumulation. In Aim 2, utilizing newly created overexpression cell lines and mouse models, a detailed mechanistic pathway by which Rbck1 deficiency results in high GS activity is tested. Additionally, aim 2 by using a novel in-vivo approach, tests the possibility of Rbck1 directly ubiquitinating long, precipitation-prone glycogen chains. Finally, in aim 3, using novel cell models and quantitative proteomics, the proposal identifies additional pathways/substrates for GS activation. Taken together, the proposed aims comprehensively study LUBAC’s function in glycogen solubility with novel understandings of its role in amylopectinosis. Deeper understandings of LUBAC mediated control of glycogen me... ## Key facts - **NIH application ID:** 10940537 - **Project number:** 1R01NS138271-01 - **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER - **Principal Investigator:** Sharmistha Mitra - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $410,000 - **Award type:** 1 - **Project period:** 2024-09-01 → 2029-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10940537 ## Citation > US National Institutes of Health, RePORTER application 10940537, Uncovering the Mechanisms of Amylopectinosis in LUBAC Deficiency (1R01NS138271-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10940537. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*