Research

Overarching Question

How do cells reprogram membrane trafficking to meet physiological demands?

Background and Mission

Over the past several decades, membrane trafficking research has uncovered the core machinery that drives membrane transport, such as coat proteins, SNAREs, and SM proteins. These core machines are conceptually analogous to RNA polymerases and transcription factors in gene expression. However, in gene regulation, the core transcriptional machinery is only part of the system. Additional regulatory layers, such as microRNAs and epigenetic mechanisms, tune gene expression in response to physiological demands.

Membrane trafficking is regulated in a similar way. Our laboratory aims to understand how trafficking behaviors—such as the speed and direction of membrane transport—are tuned by coupling trafficking machinery to broader cellular pathways, including signaling networks, chaperone systems, and metabolic states.

To achieve this goal, we focus on discovering new players that control membrane trafficking reprogramming and establishing their molecular mechanisms. We also investigate how failures in trafficking reprogramming disrupt cellular physiology and contribute to human diseases, particularly metabolic disorders. 

Key Findings

1. Vesicle Budding Regulators

We discovered CAPA (Chaperone-Assisted Adaptor Protein Assembly), a mechanism in which molecular chaperones guide the assembly of adaptor protein (AP) complexes during vesicle budding.

We identified three assembly chaperones—AAGAB, CCDC32, and MEA1—and elucidated chaperone handover and dual-chaperone collision mechanisms that regulate AP complex assembly. These mechanisms may represent general principles governing the assembly of multiprotein complexes.

2. Vesicle Fusion Regulators

We discovered the functions and molecular mechanisms of several vesicle fusion regulators, including RabIF, REPS1, and RALBP1. We also elucidated the molecular basis of previously identified trafficking factors whose mechanisms were poorly understood, including Munc18-1 (Munc18a), Munc18-3 (Munc18c), and Synip. These studies reveal new regulatory principles governing vesicle fusion. 

3. Other Trafficking Regulators

Our work has also uncovered molecular functions of regulators beyond classic vesicle budding and fusion. Examples include Extended Synaptotagmins (E-Syts), which mediate lipid transfer at membrane contact sites, and COMMD3, which regulates endosomal recycling outside the canonical Commander complex. These findings reveal how membrane trafficking is coordinated with other cellular pathways to support membrane organization and cellular physiology.

Acknowledgements

We are grateful to the funding agencies that generously support or have supported our work:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Institute of General Medical Sciences (NIGMS)

National Institute on Aging (NIA)

American Diabetes Association

Pew Charitable Trust

American Heart Association

University of Colorado Cancer Center

Cancer League of Colorado

Linda Crnic Institute for Down Syndrome

University of Colorado Boulder and Colorado State