XKR8

Summary

XKR8 (XK related 8, HGNC:25508) is a protein-coding gene on chromosome 1p35.3, encoding XK-related protein 8 (Q9H6D3). Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface.

Enables phospholipid scramblase activity. Involved in engulfment of apoptotic cell; phosphatidylserine exposure on apoptotic cell surface; and positive regulation of myoblast differentiation. Located in plasma membrane.

Source: NCBI Gene 55113 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 64 total
• MANE Select transcript: NM_018053

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25508
Approved symbol	XKR8
Name	XK related 8
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10307
Ensembl gene	ENSG00000158156
Ensembl biotype	protein_coding
OMIM	619940
Entrez	55113

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 nonsense_mediated_decay, 3 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000373884, ENST00000481387, ENST00000674618, ENST00000675282, ENST00000675359, ENST00000675575, ENST00000675759, ENST00000676017, ENST00000676058

RefSeq mRNA: 1 — MANE Select: NM_018053 NM_018053

CCDS: CCDS315

Canonical transcript exons

ENST00000373884 — 3 exons

Exon	Start	End
ENSE00001037346	27963497	27963693
ENSE00001461835	27966503	27968093
ENSE00001461837	27959973	27960362

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 97.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1666 / max 219.2924, expressed in 1591 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1766	6.0145	1588
1767	0.1520	37

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	97.08	gold quality
type B pancreatic cell	CL:0000169	96.06	gold quality
pancreatic ductal cell	CL:0002079	93.60	silver quality
oocyte	CL:0000023	93.09	gold quality
cervix squamous epithelium	UBERON:0006922	93.03	silver quality
lateral globus pallidus	UBERON:0002476	92.74	silver quality
parotid gland	UBERON:0001831	92.25	gold quality
blood	UBERON:0000178	92.21	gold quality
secondary oocyte	CL:0000655	92.19	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.03	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.45	silver quality
epithelial cell of pancreas	CL:0000083	91.35	silver quality
gluteal muscle	UBERON:0002000	90.74	gold quality
substantia nigra pars compacta	UBERON:0001965	90.63	silver quality
triceps brachii	UBERON:0001509	90.27	silver quality
nasal cavity epithelium	UBERON:0005384	90.08	gold quality
subthalamic nucleus	UBERON:0001906	90.04	silver quality
thymus	UBERON:0002370	89.89	gold quality
buccal mucosa cell	CL:0002336	89.87	silver quality
cardia of stomach	UBERON:0001162	89.58	gold quality
tongue squamous epithelium	UBERON:0006919	89.46	gold quality
synovial joint	UBERON:0002217	89.31	gold quality
tibialis anterior	UBERON:0001385	89.21	silver quality
dorsal plus ventral thalamus	UBERON:0001897	89.12	silver quality
mucosa of urinary bladder	UBERON:0001259	88.96	gold quality
inferior vagus X ganglion	UBERON:0005363	88.86	gold quality
tongue	UBERON:0001723	88.76	gold quality
body of tongue	UBERON:0011876	88.55	gold quality
penis	UBERON:0000989	88.21	gold quality
ventral tegmental area	UBERON:0002691	88.07	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

59 targeting XKR8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3714	99.71	70.74	2671

Literature-anchored findings (GeneRIF, showing 6)

• findings show the Xk-family protein Xkr8 mediates phosphatidylserine exposure in response to apoptotic stimuli; Xk-family proteins have evolutionarily conserved roles in promoting phagocytosis of dying cells by altering the phospholipid distribution in the plasma membrane (PMID:23845944)
• facilitates transbilayer migration of lipids [review] (PMID:26936867)
• Xkr8-BSG/NPTN complex is required for phosphatidylserine scrambling in apoptotic cell membranes. (PMID:27503893)
• The Xkr8 influences myogenesis by acting as a positive regulator of terminal differentiation and myoblast survival. (PMID:28881496)
• The tertiary structure of the human Xkr8-Basigin complex that scrambles phospholipids at plasma membranes. (PMID:34625749)
• The role of the C-terminal tail region as a plug to regulate XKR8 lipid scramblase. (PMID:38364890)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	xkr8.1	ENSDARG00000004498
danio_rerio	xkr8.3	ENSDARG00000039996
danio_rerio	xkr8.2	ENSDARG00000076820
danio_rerio	xkr8.4	ENSDARG00000078841
mus_musculus	Xkr8	ENSMUSG00000037752
rattus_norvegicus	Xkr8	ENSRNOG00000024312
drosophila_melanogaster	CG18635	FBGN0034279

Paralogs (5): XKR6 (ENSG00000171044), XKR4 (ENSG00000206579), XKR9 (ENSG00000221947), XKR7 (ENSG00000260903), XKR5 (ENSG00000275591)

Protein

Protein identifiers

XK-related protein 8 — Q9H6D3 (reviewed: Q9H6D3)

All UniProt accessions (6): A0A6Q8PFG6, A0A6Q8PGH8, A0A6Q8PGR5, A0A6Q8PH47, A0A6Q8PHM3, Q9H6D3

UniProt curated annotations — full annotation on UniProt →

Function. Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface. Phosphatidylserine is a specific marker only present at the surface of apoptotic cells and acts as a specific signal for engulfment. Required for the clearance of apoptotic cells, such as engulfment of apoptotic germ cells by Sertoli cells, clearance of senescent neutrophils or regulation of bipolar cell numbers in the retina. Has no effect on calcium-induced exposure of phosphatidylserine. Promotes myoblast differentiation and survival. (Microbial infection) Incorporated into Ebola virus-like particles, where its phospholipid scramblase activity is required to promote phosphatidylserine exposure on the surface of viral particles. Externalization of phosphatidylserine on the surface of viral particles is required for uptake by host cells.

Subunit / interactions. Interacts with BSG and NPTN; which act as chaperones to localize XKR8 at the cell membrane. Homodimer.

Subcellular location. Cell membrane. Cytoplasm. Perinuclear region.

Post-translational modifications. Undergoes proteolytic processing by caspase-3 (CASP3) to generate the XK-related protein 8, processed form, leading to its activation. Phosphorylation at Thr-375 activates the phospholipid scramblase activity.

Activity regulation. Activated upon caspase cleavage to generate the XK-related protein 8, processed form. Does not act prior the onset of apoptosis.

Miscellaneous. Expression is repressed in PLB-985 leukemia and Raji lymphoma cells due to CpG methylation near the transcription start site of XKR8 gene, possibly explaining the inability of PLB-985 leukemia and Raji lymphoma cells to expose phosphatidylserine during apoptosis.

Similarity. Belongs to the XK family.

RefSeq proteins (1): NP_060523* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018629	XK-rel	Family
IPR050895	XK-related_scramblase	Family

Pfam: PF09815

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) (RHEA:38663)

UniProt features (23 total): topological domain 9, transmembrane region 8, chain 2, modified residue 2, site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8XEJ	ELECTRON MICROSCOPY	3.66
7DCE	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6D3-F1	82.45	0.45

Antibody-complex structures (SAbDab): 2 — 7DCE, 8XEJ

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 355–356 (cleavage; by caspase-3)

Post-translational modifications (2): 362, 375

Mutagenesis-validated functional residues (1):

Position	Phenotype
352–355	in 2da; abolished cleavage by casp3 and ability to promote phosphatidylserine exposure. does not affect interaction with

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 164 (showing top): GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_TOLERANCE_INDUCTION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_APOPTOTIC_CELL_CLEARANCE, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, NFKB_Q6, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_REGULATION_OF_MYOBLAST_DIFFERENTIATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_MYOBLAST_DIFFERENTIATION, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_APOPTOTIC_PROCESS_INVOLVED_IN_DEVELOPMENT

GO Biological Process (8): tolerance induction to self antigen (GO:0002513), engulfment of apoptotic cell (GO:0043652), positive regulation of myoblast differentiation (GO:0045663), establishment of localization in cell (GO:0051649), phosphatidylserine exposure on apoptotic cell surface (GO:0070782), neutrophil clearance (GO:0097350), apoptotic process involved in development (GO:1902742), apoptotic process (GO:0006915)

GO Molecular Function (1): phospholipid scramblase activity (GO:0017128)

GO Cellular Component (4): plasma membrane (GO:0005886), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
apoptotic cell clearance	2
plasma membrane phospholipid scrambling	2
execution phase of apoptosis	2
tolerance induction	1
phagocytosis, engulfment	1
myoblast differentiation	1
positive regulation of cell differentiation	1
regulation of myoblast differentiation	1
establishment of localization	1
cellular localization	1
phospholipid scramblase activity	1
neutrophil homeostasis	1
phagocytosis	1
apoptotic process	1
anatomical structure development	1
programmed cell death	1
apoptotic signaling pathway	1
intramembrane lipid carrier activity	1
membrane	1
cell periphery	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

406 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XKR8	ATP11C	Q8NB49	831
XKR8	ANO6	Q4KMQ2	800
XKR8	NPTN	Q9Y639	696
XKR8	ATP11A	P98196	672
XKR8	CDC50A	Q9NV96	580
XKR8	BSG	P35613	566
XKR8	ADGRB1	O14514	513
XKR8	TIMD4	Q96H15	510
XKR8	XK	P51811	505
XKR8	PLSCR1	O15162	499
XKR8	GULP1	Q9UBP9	490
XKR8	MFGE8	Q08431	475
XKR8	STAB2	Q8WWQ8	453
XKR8	HYLS1	Q96M11	446
XKR8	ATP8A2	Q9NTI2	428

IntAct

9 interactions, top by confidence:

A	B	Type	Score
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
XKR8	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CFTR	XKR8	psi-mi:“MI:0915”(physical association)	0.370
PTGIR	GPAA1	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): XKR8 (Reconstituted Complex), XKR8 (Affinity Capture-MS), XKR8 (Affinity Capture-MS), XKR8 (Affinity Capture-MS), XKR8 (Affinity Capture-MS), XKR8 (Affinity Capture-MS), XKR8 (Affinity Capture-MS), XKR8 (PCA)

ESM2 similar proteins: A0A8C2M425, A1L1J9, A1L504, A6NH21, A8WCG0, B0BNG2, F1RMN2, O43292, O75908, O76062, O77759, O88496, O88908, O89109, P38435, Q07175, Q0P4Y8, Q49LS0, Q5KR61, Q5RF50, Q5XK03, Q5ZKZ9, Q643R3, Q658P3, Q6MG14, Q6NVG1, Q767L9, Q7TN60, Q7TPN3, Q7TQM4, Q7ZWN0, Q8BKF1, Q8C3X8, Q8IUH8, Q8IZY2, Q8N130, Q8VC65, Q8WMV1, Q91YD1, Q9BU23

Diamond homologs: Q49LR9, Q49LS0, Q49LS3, Q49LS6, Q5GH62, Q5GH70, Q9H6D3, Q49LS7, Q49LS8, Q4VV71, Q5GH59, Q5GH64, Q8C0T0, E9Q6C8, Q49LS1, Q49LS4, Q49LS9, Q5GH56, Q5GH57, Q5GH66, Q5GH67, Q5GH72, Q5GH73, Q5GH76, Q6UX68, A8Y2U2, O17386

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

64 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

712 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27960359:ACAGG:A	donor_loss	1.0000
1:27960361:AGG:A	donor_loss	1.0000
1:27960363:G:GA	donor_loss	1.0000
1:27963483:T:TA	acceptor_gain	1.0000
1:27963485:T:TA	acceptor_gain	1.0000
1:27963487:T:TA	acceptor_gain	1.0000
1:27963488:G:A	acceptor_gain	1.0000
1:27963493:CTA:C	acceptor_loss	1.0000
1:27963494:TA:T	acceptor_loss	1.0000
1:27963496:G:GA	acceptor_loss	1.0000
1:27963676:GGGC:G	donor_gain	1.0000
1:27963677:GGC:G	donor_gain	1.0000
1:27963678:GC:G	donor_gain	1.0000
1:27963679:C:CG	donor_gain	1.0000
1:27963679:C:G	donor_gain	1.0000
1:27963689:CCAGT:C	donor_gain	1.0000
1:27963690:CAGT:C	donor_gain	1.0000
1:27963692:GT:G	donor_gain	1.0000
1:27963694:G:C	donor_loss	1.0000
1:27963694:G:GG	donor_gain	1.0000
1:27963697:A:AG	donor_gain	1.0000
1:27963698:G:GG	donor_gain	1.0000
1:27966497:TTGCA:T	acceptor_loss	1.0000
1:27966498:TGCA:T	acceptor_loss	1.0000
1:27966499:GCAG:G	acceptor_loss	1.0000
1:27966500:CAG:C	acceptor_loss	1.0000
1:27966501:A:AG	acceptor_gain	1.0000
1:27966501:AG:A	acceptor_gain	1.0000
1:27966501:AGG:A	acceptor_gain	1.0000
1:27966501:AGGG:A	acceptor_gain	1.0000

AlphaMissense

2485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27960259:A:C	S64R	0.974
1:27960261:C:A	S64R	0.974
1:27960261:C:G	S64R	0.974
1:27966898:A:C	S296R	0.972
1:27966900:C:A	S296R	0.972
1:27966900:C:G	S296R	0.972
1:27966721:T:A	W237R	0.961
1:27966721:T:C	W237R	0.961
1:27966829:T:A	W273R	0.961
1:27966829:T:C	W273R	0.961
1:27963618:T:C	F139L	0.960
1:27963620:C:A	F139L	0.960
1:27963620:C:G	F139L	0.960
1:27960362:G:T	R98M	0.956
1:27966823:T:C	F271L	0.956
1:27966825:C:A	F271L	0.956
1:27966825:C:G	F271L	0.956
1:27966739:T:A	W243R	0.953
1:27966739:T:C	W243R	0.953
1:27966628:T:A	W206R	0.950
1:27966628:T:C	W206R	0.950
1:27967000:G:C	G330R	0.947
1:27966833:T:C	F274S	0.943
1:27963589:A:T	D129V	0.942
1:27963576:T:C	F125L	0.941
1:27963578:C:A	F125L	0.941
1:27963578:C:G	F125L	0.941
1:27966809:C:A	A266D	0.940
1:27963640:T:C	L146P	0.938
1:27963634:C:G	P144R	0.935

dbSNP variants (sampled 300 via entrez): RS1000692778 (1:27961927 A>G), RS1000746227 (1:27961554 C>T), RS1001531251 (1:27958854 T>C), RS1001749762 (1:27963147 C>G), RS1002698822 (1:27965274 CA>C), RS1002750948 (1:27964937 C>T), RS1003640727 (1:27960026 G>T), RS1004611258 (1:27961125 A>C,T), RS1004771810 (1:27967513 C>T), RS1005530797 (1:27959698 C>A), RS1005865487 (1:27958372 T>A,C), RS1006402043 (1:27958459 C>G,T), RS1006536266 (1:27958076 G>T), RS1006692988 (1:27963895 G>T), RS1007562014 (1:27965944 G>A)

Disease associations

OMIM: gene MIM:619940 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	2
Particulate Matter	increases methylation, decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
bisphenol S	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Smoke	decreases expression	1
Urethane	increases expression	1
Vitamin E	increases expression	1
Sodium Selenite	increases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_DX24	HAP1 ANO6 (-) XKR8 (-) 1	Cancer cell line	Male
CVCL_DX25	HAP1 ANO6 (-) XKR8 (-) 2	Cancer cell line	Male
CVCL_DX26	HAP1 ANO6 (-) XKR8 (-) 3	Cancer cell line	Male
CVCL_DX27	HAP1 ANO6 (-) XKR8 (-) 4	Cancer cell line	Male
CVCL_TY32	HAP1 XKR8 (-) 1	Cancer cell line	Male
CVCL_XV16	HAP1 XKR8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.