# Hermansky Pudlak syndrome & melanosome formation

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $478,640

## Abstract

The Hermansky-Pudlak syndromes (HPS) are heritable diseases characterized by oculocutaneous albinism
(with associated visual impairment and susceptibility to skin and ocular cancers), excessive bleeding and other
variable symptoms. The symptoms reflect the malformation of cell type-specific lysosome-related organelles
(LROs) such as melanosomes, the organelles of skin and ocular pigment cells within which melanin pigments
are synthesized. The genes that are defective in HPS and its mouse models encode subunits of five protein
complexes – Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2 and -3, AP-3 and HOPS –
that regulate membrane trafficking during LRO maturation. This proposal seeks to define how these complexes
cooperate to regulate transport to and from melanosomes of fusion proteins, or SNAREs, and thereby define
the essential roles of these proteins in fusion events during the biogenesis of melanosomes and other LROs.
Most newly synthesized melanogenic membrane proteins are delivered to maturing melanosomes via tubular
transport carriers that form from early endosomes in a BLOC-1-dependent manner and that are then targeted
to maturing melanosomes by BLOC-2. These transport carriers harbor the SNARE subunit syntaxin 13
(STX13), but STX13 is not incorporated into the melanosome membrane and thus does not likely drive tubule
fusion with melanosomes. Rather, the vesicular SNARE VAMP7 drives fusion, but how either SNARE is sorted
into the transport carriers and how STX13 and VAMP7 are segregated during fusion with melanosomes is not
known. We hypothesize that: (1) cis-SNARE complexes containing VAMP7 and STX13 are sorted from early
endosomes into the tubules via partially redundant interactions with BLOC-1 and AP-3; (2) this complex is
dissembled at the maturing melanosome; and (3) HOPS stabilizes a complex containing VAMP7 and a distinct
syntaxin, permitting transient fusion of the tubules with melanosomes and allowing inactive STX13 to return to
endosomes upon tubule retraction. After the carriers fuse, VAMP7 – now on melanosomes – must be returned
to its endosomal site of origin to participate in new rounds of forward transport. Based on preliminary data, we
hypothesize that (4) VAMP7 is recycled from melanosomes in distinct tubular structures via BLOC-3-
dependent recruitment of cytoskeletal motors, including Myosin VI. Our hypotheses create a unifying model for
the involvement of all HPS protein complexes in SNARE cycling between endosomes and melanosomes that
should apply to all LRO-containing cell types, and might explain how promiscuous endosomal SNARE
interactions are regulated to promote directional membrane transport among distinct endosomal compartments
in all vertebrate cells. Our Specific Aims are: 1. to test whether AP-3 and BLOC-1 cooperate in SNARE
complex sorting into melanosome-bound tubules; 2. to test whether HOPS facilitates SNARE formation
during BLOC-1-dependent melanosome maturation; and 3. to test whether...

## Key facts

- **NIH application ID:** 10011806
- **Project number:** 5R01EY015625-15
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael S Marks
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $478,640
- **Award type:** 5
- **Project period:** 2004-05-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011806

## Citation

> US National Institutes of Health, RePORTER application 10011806, Hermansky Pudlak syndrome & melanosome formation (5R01EY015625-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10011806. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*