The team of Chen Caiyong of the Chinese Academy of Biosciences published a paper in Nature to reveal a new intracellular heme chaperone protein...

Heme (Heme) is a class of porphyrin compounds
that contain iron ions.
In addition to binding oxygen in hemoglobin, it is also a cofactor for myoglobin, cytochrome, cytochrome P450, catalase, peroxidase and other proteins, and participates in the regulation of gene expression, miRNA processing, circadian rhythm and other processes
。 Intracellular heme originates from the mitochondria at the site of synthesis or the cell membrane at the site of absorption, and proteins that require heme are widely distributed in various subcellular sites, and free heme is hydrophobic and cytotoxic, so cells need to rely on specific transporters to transport and utilize heme ^[1,2].
】
。

On October 19, 2022, the Chen Caiyong Laboratory of the College of Life Sciences, Zhejiang University published a paper in Nature The HRG-9 homologues regulate haem trafficking from haem-enriched compartments reveals a new intracellular heme chaperone protein HRG-9 (heme responsive gene-9).
）
。 In C.
elegans, HRG-9 and its homologous protein HRG-10 transport heme out of its storage site, lysosome-associated organelles; In humans, zebrafish, yeast and other organisms that can synthesize heme on their own, the homologous protein of HRG-9, Tango2, transports heme out of its synthesis site
, the mitochondria.

To study the heme transport pathway, the researchers first performed a genetic screening
on the model animal, C.
elegans.
C.
elegans is a trophically deficient heme animal that cannot synthesize heme itself, but there are a variety of proteins that require heme ^[3].

C.
elegans relies entirely on transport systems for heme ingestion, making it an ideal model for
studying heme transport.
The researchers discovered a new heme-sensing gene, HRG-9
, through transcriptomic analysis.
After deletion of HRG-9 and/or its homologous gene HRG-10 in nematodes, heme accumulates in large quantities at the storage site, lysosome-associated organelles, while other subcellular sites are ischemic in heme Indicates C.
elegans HRG-9 and HRG-10 transport heme out of the storage site for cellular use
.

HRG-9 has a homologous gene in other species called Tango2, which was originally thought to be involved in regulating protein transport and Golgi structure [4].
^】
。 To determine whether Tango2 also regulates heme homeostasis, the researchers looked at the Tango2 gene in yeast, zebrafish, and mammals Studies were carried out.

The results showed that expressing yeast, zebrafish or human tango2 could rescue heme transport defects caused by the deletion of HRG-9/HRG-10 in nematodes, namely Tango2 and HRG-9 have similar functions in the regulation of heme homeostasis.

After the loss of tango2 in yeast and mammalian cells, heme accumulates in the mitochondria at
the site of synthesis.
Biochemical experiments showed that Tango2 protein binds to heme and transfers heme out of mitochondria
.

Pattern diagram of HRG-9 and its homologous protein transporter heme

Mutations in the human Tango2 gene cause a rare genetic disorder ^{[5, 6 】}
。 The patients who have been reported are all children, and the patients have a variety of symptoms
such as developmental delay, rhabdomyolysis, arrhythmia, epilepsy, and metabolic syndrome.
At present, the cause of the disease caused by the Tango2 mutation is still unclear
.
The researchers found that tango2 in zebrafish is also crucial
for early growth and development.
After knocking out Tango2 on zebrafish, juveniles exhibit encephalopathy, arrhythmias, muscle damage, and die early in development, with phenotypes similar
to those in diseased children.
Therefore, the mutant zebrafish provides a disease model
for studying the pathogenesis and treatment strategies of Tango2 disease.

This study is the first to discover intracellular heme chaperones HRG-9 and Tango2, and reveals an important mechanism of heme transport and utilization in cells; At the same time, the biological function of Tango2 in heme metabolism was elucidated, which provided a basis
for exploring the pathological mechanism of Tango2 disease.

The research work was completed by the Chen Caiyong Laboratory of the College of Life Sciences, Zhejiang University, with Sun Fengxiu and Zhao Zhenzhen, doctoral students in Chen Caiyong's group as the co-first authors of the paper, Shen Shuaiqi, Zhou Yu and other students, and Amit Reddi of Georgia Institute of Technology The lab and Iqbal Hamza's lab at the University of Maryland were involved in the work
.
The study was supported
by the National Foundation of China, the Ministry of Science and Technology, the Cancer Research Institute of Zhejiang University and the National Institutes of Health.

Photojournalist | Lu Shaoqing

Original link: https://doi.
org/10.
1038/s41586-022-05347-z

References:

1.
Severance, S.
& Hamza, I.
Trafficking of heme and porphyrins in metazoa.
Chem.
Rev.
109, 4596–4616 (2009).

2.
Reddi, A.
R.
& Hamza, I.
Heme mobilization in animals: a metallolipid’s journey.
Acc.
Chem.
Res.
49, 1104–1110 (2016).

3.
Rao, A.
U.
, Carta, L.
K.
, Lesuisse, E.
& Hamza, I.
Lack of heme synthesis in a free-living eukaryote.
Proc.
Natl Acad.
Sci.
USA 102, 4270–4275 (2005).

4.
Bard, F.
et al.
Functional genomics reveals genes involved in protein secretion and Golgi organization.
Nature 439, 604–607 (2006).

5.
Kremer, L.
S.
et al.
Bi-allelic truncating mutations in TANGO2 cause infancy-onset recurrent metabolic crises with encephalocardiomyopathy.
Am.
J.
Hum.
Genet.
98, 358–362 (2016).

6.
Lalani, S.
R.
et al.
Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic TANGO2 mutations.
Am.
J.
Hum.
Genet.
98, 347–357 (2016).