# Role of the autophagy-inducing kinases ULK1/2 in ER export and protein trafficking

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $448,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Unc51-like kinases 1 and 2 (ULK1/2) are best characterized for their roles in autophagy, an evolutionarily
conserved response to starvation that allows cells to recycle cellular components. We recently discovered that,
in addition to their well-established roles in autophagy, ULK1/2 regulate endoplasmic reticulum (ER)-to-Golgi
trafficking. This molecular connection between autophagy and COPII transport may answer the long-standing
question as to what mechanism(s) underlie the differential export of secretory cargoes from the ER in response
to metabolic cues. Because ULK1/2 regulates ER-to-Golgi trafficking under basal conditions, initiates
autophagosome formation near ERESs in response to metabolic stress, and is a direct target of nutrient- and
energy-sensing kinases (i.e., mTOR and AMPK), it is poised to coordinate metabolic cues and protein
trafficking from the ER. Our preliminary studies suggest that cargoes destined for the plasma membrane are
differentially trafficked in response to metabolic stress, and this switch may depend on ULK1/2 activity. ER
export of some cargoes (exemplified by the serotonin transporter SERT) decreases in response to metabolic
stress, whereas trafficking of other cargoes (exemplified by the amino acid transporter CD98) increases.
Although nutrient-dependent ER export is of importance to a broad range of cell types, the potential
implications of ULK1/2's role in regulating this process are immediately relevant in serotonergic neurons, which
not only rely on SERT to terminate serotonergic neurotransmission but also rely on the regulated uptake of
amino acids by CD98 for serotonin production. Serotonin signaling is linked to nutrient availability, and
dysregulation of serotonin signaling leads to perturbations in neuronal circuits that increase the risk of
developing neuropsychiatric disorders, including autism, schizophrenia, depression, and eating disorders. This
proposal seeks to answer the following questions from the perspective of ULK1/2: How is COPII-dependent
ER-to-Golgi trafficking suppressed in response to nutrient deprivation? How does nutrient deprivation stimulate
the ER export of certain cargoes? Defining ULK1/2 as a potential mechanistic link between nutrient availability
and key aspects of serotonergic neurotransmission – namely, SERT-mediated serotonin reuptake and the
production of serotonin via CD98-mediated Trp uptake – may provide a model of how neurons coordinate
metabolic signals with neurotransmission to maintain homeostasis.

## Key facts

- **NIH application ID:** 9974591
- **Project number:** 5R01MH115058-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** MONDIRA KUNDU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,750
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974591

## Citation

> US National Institutes of Health, RePORTER application 9974591, Role of the autophagy-inducing kinases ULK1/2 in ER export and protein trafficking (5R01MH115058-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974591. Licensed CC0.

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