Engineered TSC2 Phosphorylation Control for Immune Cell mTORC1
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Solution Overview
Problem
Current methods for modulating mechanistic target of rapamycin complex 1 (mTORC1) signaling are broad and risk compromising its normal physiological functions, while disease-specific modulation is lacking, particularly in immune cells where mTORC1 hyperactivation leads to autoimmune disorders and cancer.
Innovation Solution
Engineered TSC2 polypeptides with altered phosphorylation residues, such as S1365 and S1364, to either prevent or mimic phosphorylation, allowing precise control of mTORC1 signaling in immune cells, enhancing their function and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If broad suppression of mTORC1 is applied, then disease-related hyperactivation is reduced, but normal physiological functions are compromised
Solution Approach 1:
The patent applies local quality by creating disease-specific modulation rather than broad suppression. Engineered TSC2 polypeptides with specific phosphorylation site mutations (S1365A, S1364A) are designed to target mTORC1 regulation in specific disease contexts, particularly in immune cells, thereby reducing harmful hyperactivation while preserving normal physiological functions through selective and localized intervention
2Object-affected harmful factors
If multiple kinase sites are silenced to block enzyme effects, then specific kinase activity is reduced, but device complexity increases
Solution Approach 1:
The patent extracts the regulatory function from complex multi-kinase systems by focusing on a single engineered TSC2 polypeptide with specific phosphorylation site mutations. This isolated approach allows control of mTORC1 signaling through one modified protein rather than coordinating multiple kinase inhibitions, significantly reducing system complexity while maintaining specific regulatory activity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered TSC2 polypeptides enable targeted modulation of mTORC1 activity, improving immune cell function and persistence, and treating diseases like cancer and autoimmune disorders by enhancing or reducing cytokine expression and cell memory.
Implementation Method 1
an engineered TSC2 polypeptide in which the ability of a residue (e.g., a residue corresponding to a serine residue in a wild type TSC2 polypeptide) to be phosphorylated is altered
Data Source
AI summary
Provided herein are engineered tuberous sclerosis complex 2 (TSC2) polypeptides in which the ability of a residue corresponding to a serine residue in a wild type TSC2 polypeptide to be phosphorylated is altered. In some cases, an engineered TSC2 polypeptide cannot be phosphorylated (e.g., by substituting a serine residue with an alanine residue). In some cases, an engineered TSC2 polypeptide can act as if it is constitutively phosphorylated (e.g., by substituting a serine residue with a glutamic acid residue). Also provided herein are engineered immune cells including altered TSC2 polypeptides or including nucleic acid sequences encoding altered TSC2 polypeptides, and methods of making and using such engineered immune cells.