{{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''Kelch-Like Protein 36''' (abbreviated KLHL36) is a protein that in humans is encoded by the ''KLHL36'' gene.<ref name="NCBI">{{Cite web | title = KLHL36 kelch like family member 36 [Homo sapiens (human)] - Gene - NCBI | url = https://www.ncbi.nlm.nih.gov/gene/79786 | access-date = 2025-09-11 | work = National Center for Biotechnology Information }}</ref> Although the gene's specific function has yet to be characterized, it is predicted to serve as a substrate adaptor for Cullin-RING E3 ubiquitin ligase (CRL3) complexes, contributing to proteostasis.<ref name="Zhou_2024">{{cite journal | vauthors = Zhou Y, Zhang Q, Zhao Z, Hu X, You Q, Jiang Z | title = Targeting kelch-like (KLHL) proteins: achievements, challenges and perspectives | journal = European Journal of Medicinal Chemistry | volume = 269 | date = April 2024 | pmid = 38490062 | doi = 10.1016/j.ejmech.2024.116270 | article-number = 116270 }}</ref> == Gene == In humans, the KLHL 36 gene consists of 5 exons and 4 introns spanning 19,176 base pairs on the positive strand of chromosome 16 (16q24.1).<ref name="NCBI" />
The gene is a member of the Kelch-like gene family, which is characterized by a conserved BTB-BACK-Kelch domain architecture. Kelch-like genes encode proteins that recognize and bind specific protein substrates, bind the scaffold protein cullin 3 in the CRL3 complex, and pass the substrate protein to the complex to facilitate ubiquitylation and degradation at the proteasome.<ref name="Zhou_2024" /> [[File:KLHL36 Locus, Genome.png|thumb|522x522px|'''Figure 1.''' KLHL36 location on Chromosome 16 in ''Homo sapiens''. KLHL36 is surrounded by two protein coding genes, USP10 downstream on the positive strand, and COTL1 upstream on the negative strand.|none]] == Homology ==
=== Orthologs === The KLHL36 gene is highly conserved in vertebrates. Orthologs of KLHL36 are present in jawed vertebrates tracing back to cartilaginous fishes, although no orthologs have been identified in jawless vertebrates or invertebrates.<ref>{{Cite web | title = National Library of Medicine | date = September 27, 2025 | url = https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins | access-date = September 9, 2025 | website = NCBI Protein Blast }}</ref> This suggests that the KLHL36 gene originated in a common ancestor of jawed vertebrates roughly 462 millions years ago.<ref>{{cite journal | vauthors = Kumar S, Stecher G, Suleski M, Hedges SB | title = TimeTree: A Resource for Timelines, Timetrees, and Divergence Times | journal = Molecular Biology and Evolution | volume = 34 | issue = 7 | pages = 1812–1819 | date = July 2017 | pmid = 28387841 | doi = 10.1093/molbev/msx116 }}</ref>
KLHL is remarkably conserved across jawed vertebrates, sharing a greater than 77 percent sequence identity with many species of cartilaginous fishes, whose lineages diverged from that of humans roughly 462 million years ago. KLHL36 orthologs are summarized in '''Table 1'''.
{| class="wikitable sortable" |+Table 1. Divergence of Selected Orthologs of Human KLHL36 !Genus and species !Common name !Taxonomic group !Median Date of Divergence (Millions of Years ago) !Accession # !Sequence length (aa) !Sequence identity to human protein (%) !Sequence similarity to human protein (%) |- |''Homo sapiens'' |Humans |Hominidae |0 |NP_079007.2 |616 |100 |100 |- |''Pan paniscus'' |Bonobo |Hominidae |6.4 |XP_054956502.1 |616 |99.8 |100 |- |''Nasalis larvatus'' |Proboscis Monkey |Primata |28.8 |KAL4835633.1 |616 |99.2 |99.7 |- |''Mus musculus'' |House Mouse |Rodentia |87 |NP_666331.1 |613 |85.7 |92.2 |- |''Canis lupus familiaris'' |Domestic Dog |Carnivora |94 |XP_005620696.2 |616 |96.8 |98.5 |- |''Physeter macrocephalus'' |Sperm Whale |Artiodactyla |94 |XP_023980819.1 |616 |96.1 |97.7 |- |''Notamacropus eugenii'' |Tamar Wallaby |Marsupialia |160 |XP_072492309.1 |615 |89.8 |94.6 |- |''Ornithorhynchus anatinus'' |Platypus |Monotremata |180 |XP_001509771.2 |616 |87.2 |92.9 |- |''Gallus gallus'' |Red Junglefowl |Aves |319 |XP_040537292.1 |615 |85.4 |92 |- |''Dermochelys coriacea'' |Leatherback Sea Turtle |Reptilia |319 |XP_038224216.1 |615 |85.1 |92.4 |- |''Alligator sinensis'' |Chinese Alligator |Reptilia |319 |XP_006022804.1 |615 |85.1 |92.5 |- |''Geotrypetes seraphini'' |Gaboon Caecilian |Amphibia |352 |XP_033796775.1 |615 |80.4 |89.3 |- |''Eleutherodactylus coqui'' |Common Coqui |Amphibia |352 |XP_066439605.1 |615 |72.4 |83.8 |- |''Ambystoma mexicanum'' |Axolotl |Amphibia |352 |XP_069492346.1 |615 |72.9 |85.6 |- |''Latimeria chalumnae'' |West Indian Ocean Coelacanth |Sarcopterygii |415 |XP_069492346.1 |614 |78.7 |87.5 |- |''Thalassophryne amazonica'' |Amazon Toadfish |Actinopterygii |429 |XP_034031579.1 |611 |56.4 |70.7 |- |''Danio rerio'' |Zebrafish |Actinopterygii |429 |NP_001018416.3 |610 |61 |74.6 |- |''Hypanus sabinus'' |Atlantic Stingray |Chondrychthytes |462 |XP_059849157.1 |612 |77.8 |86.9 |- |''Callorhinchus milii'' |Australian Ghostshark |Chondrychthytes |462 |XP_042196266.1 |615 |78.2 |85.8 |- |''Scyliorhinus canicula'' |Small Spotted Catshark |Chondrychthytes |462 |XP_038662242.1 |612 |77.3 |85.9 |} [[File:KLHL36 divergence graph.png|thumb|444x444px|'''Figure 2. KLHL36 Corrected number of amino acid changes over evolutionary history.''' Cytochrome c represents a highly conserved control, and Fibrinogen alpha represents a poorly conserved control. ]]Among the 20 selected orthologs, the amino acid identity at a given position was conserved in all orthologs at 35.4% of positions.
'''Figure 2''' shows the divergence of KLHL36 in terms of corrected number of amino acid changes over millions of years. KLHL36 is remarkably highly conserved, similar to cytochrome c, with minimal changes in amino acid composition over time.<ref>{{Cite web | title = CYCS cytochrome c, somatic [Homo sapiens (human)] - Gene - NCBI | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=54205 | access-date = 2025-12-12 | website = www.ncbi.nlm.nih.gov }}</ref><ref>{{Cite web | title = FGA fibrinogen alpha chain [Homo sapiens (human)] - Gene - NCBI | url = https://www.ncbi.nlm.nih.gov/gene/2243 | access-date = 2025-12-12 | website = www.ncbi.nlm.nih.gov }}</ref> Corrected amino acid changes are calculated as 100 * ln(1 - (M/100)), where M represents the observed number of amino acid changes per hundred amino acids in selected orthologs of KLHL36.
=== Paralogs === 54 paralogs of KLHL36 have been identified, with its closest relatives being KLHL13 and KLHL26.<ref name="UniProt_Q8N4N3">{{Cite web | title = UniProt | url = https://www.uniprot.org/uniprotkb/Q8N4N3/entry | access-date = 2025-09-28 | website = UniProt | language = en }}</ref> The KLHL family of genes contains 42 genes from KLHL1 to KLHL42. Paralogs of KLHL36 are summarized in '''Table 2'''. {| class="wikitable" |+Table 2. Identity and Similarity of KLHL36 Most Closely Related Relatives !Gene/Paralog (Isoform) !Sequence Length (Amino Acids) !Query Coverage !Percent Identity Match !Percent Similarity Match !Number of Isoforms !Accession Number |- |KLHL36 (1) |616 |100 |100 |100 |3 |NP_079007.2 |- |KLHL13 (e) |604 |94 |38 |60 |7 |NP_001161775.2 |- |KLHL26 (3) |604 |94 |36 |55 |6 |NP_001332911.1 |- |KLHL32 (n) |556 |84 |34 |51 |15 |NP_001310192.1 |- |KLHL22 |634 |96 |33 |51 |9 |NP_116164.2 |- |KLHL31 |634 |93 |32 |52 |1 |NP_001003760.2 |- |KLHL14 |628 |91 |31 |51 |2 |NP_116164.2 |- |KLHL34 |644 |94 |29 |45 |1 |NP_695002.1 |- |KLHL18 |574 |88 |29 |47 |1 |NP_079286.2 |- |KLHL15 |604 |89 |29 |47 |1 |NP_085127.2 |- |KLHL2 (1) |593 |89 |28 |49 |5 |NP_009177.3 |- |KLHL 3 (2) |555 |90 |28 |49 |3 |NP_001244123.1 |- |KEAP1 |624 |93 |28 |43 |1 |NP_036421.2 |- |KLHL17 |642 |93 |27 |46 |6 |NP_938073.1 |- |KLHL1 (1) |748 |83 |27 |44 |4 |NP_065917.1 |- |KLHL12 (1) |606 |92 |27 |43 |9 |NP_001289980. |- |KLHL10 (1) |608 |92 |27 |43 |2 |NP_001316524.1 |- |KLHL28 (1) |585 |91 |27 |42 |6 |NP_001295041. |- |KLHL25 |589 |94 |27 |42 |1 |NP_071925.2 |}
== Expression == [[File:KLHL36 expression graph.png|thumb|470x470px|'''Figure 3. Graph of KLHL36 Expression Across Tissues.'''<ref name="Fagerberg_2014">{{cite journal | vauthors = Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M | title = Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics | journal = Molecular & Cellular Proteomics | volume = 13 | issue = 2 | pages = 397–406 | date = February 2014 | pmid = 24309898 | pmc = 3916642 | doi = 10.1074/mcp.M113.035600 | doi-access = free }}</ref> RPKM, or reads per kilobase per million reads, is a normalized measure of gene expression from RNA sequencing.]] KLHL36 is expressed ubiquitously at moderate levels across all tissues, with moderate variation across tissues.<ref name="NCBI" /> The highest expression of the protein is observed in the testes, fat, and thyroid.<ref name="Fagerberg_2014" />
Whole body transcriptomic tissue analyses have revealed that, while KLHL36 is expressed at its highest absolute values in the testes, fat, and thyroid, it is expressed at its highest levels relative to other proteins in cells of the immune system, such as B cells, T cells, and monocytes.<ref>{{cite journal | vauthors = Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB | title = A gene atlas of the mouse and human protein-encoding transcriptomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 16 | pages = 6062–6067 | date = April 2004 | pmid = 15075390 | pmc = 395923 | doi = 10.1073/pnas.0400782101 | doi-access = free | bibcode = 2004PNAS..101.6062S }}</ref>
== Transcript == There are 6 known transcript variants of KLHL36, the most common transcript variant being transcript variant 1. Transcript variant 1 encodes the longest and most common isoform, isoform 1.<ref name="NCBI" /> Transcript variant 1 is 7,559 nucleotides in length and contains 5 exons.<ref name="NCBI" /> Its 5' untranslated region is 158 nucleotides in length and its 3' untranslated region is 5,556 nucleotides in length.
Transcript Variants X1 and X2 contain the same coding sequence and encode an identical protein to transcript variant 1, with slightly differing 5' untranslated regions. Transcript Variant 2 encodes a slightly different protein product, missing part of the internal amino acid sequence but with the Kelch motifs at the C terminal intact. Transcript Variant X4 is significantly truncated, missing a large portion of the coding sequence and the 3' UTR and containing no Kelch motifs. Transcript Variants of KLHL36 and their corresponding protein isoforms are summarized in '''Table 3'''.<ref name="NCBI" /> {| class="wikitable" |+Table 3. ''Homo sapiens'' KLHL36 Transcript Variants and Corresponding Protein Isoforms !Transcript Variant !Accession Number !Length (Nucleotides) !Exon Count !Corresponding Protein Isoform !Accession Number !Amino Acid Length |- |Transcript Variant 1 |NM_024731.4 |7559 |5 |Protein Isoform 1 |NP_079007.2 |616 |- |Transcript Variant X1 |XM_047434648.1 |7547 |5 |Protein Isoform X1 |XP_047290604.1 |616 |- |Transcript Variant X2 |XM_005256149.3 |7503 |5 |Protein Isoform X1 |XP_005256206.1 |616 |- |Transcript Variant X3 |XM_047434649.1 |7797 |5 |Protein Isoform X1 |XP_047290605.1 |616 |- |Transcript Variant 2 |NM_001303451.2 |7370 |4 |Protein Isoform 2 |NP_001290380.1 |553 |- |Transcript Variant X4 |XM_047434650.1 |1380 |4 |Protein Isoform X2 |XP_047290606.1 |372 |} Many RNA binding proteins are predicted to bind to the 5' UTR KLHL36 Transcript Variant 1 mRNA, including YBX1, Vts1, RBM4, KHSRP, and RBMX.<ref name="cite82d338ef">{{Cite web | title = RBPDB: The database of RNA-binding specificities | url = http://rbpdb.ccbr.utoronto.ca/ | access-date = 2025-12-12 | website = rbpdb.ccbr.utoronto.ca }}</ref> Several additional RNA binding proteins are predicted to bind to the 3' UTR, including YBX1, PUM2, EIF4B, MBNL2, ACO1, KHSRP, RBMY1A1, SFRS13A, YTHDC1, ELAVL1, FUS, ZRANB2, PABPC1, and SFRS9.<ref name="cite82d338ef" /> RNA binding proteins that are predicted to bind the promoter of KLHL36 include ZNF667, ZNF530, ZIC4, SNF257, TFAP2A, TFAP2C, ZTBT24, KLF10, KLF12, SREBF1, KLF5, ZVED4, and NFYB.<ref name="cite82d338ef" />
'''Figure 4''' consists of a conceptual translation of KLHL36 Transcript Variant 1 coding sequence, which demonstrates the layout of the mRNA and the corresponding amino acids, protein domains, and exon boundaries.<ref name="NCBI" /> [[File:KLHL36 conceptual translation a.png|thumb|947x947px|none|'''Figure 4a. Conceptual Translation of KLHL36 Transcript Variant 1 mRNA, including BTB/POZ domain, BACK domain, Kelch Motifs, start and stop codons, and exon boundaries.''']] [[File:KLHL36 conceptual translation b.png|none|thumb|946x946px|'''Figure 4b. Conceptual Translation of KLHL36 Transcript Variant 1 mRNA, including 3' UTR, polyA signal sequences, and major polyadenylation sites.''']]
== Protein == thumb|374x374px|'''Figure 3. AlphaFold v4 predicted tertiary structure of ''Homo sapiens'' KLHL36 protein isoform 1.<ref>{{Cite web | title = AlphaFold Protein Structure Database | url = https://alphafold.ebi.ac.uk/entry/Q8N4N3 | access-date = 2025-09-26 | website = alphafold.ebi.ac.uk }}</ref>'''There are 3 protein isoforms of KLHL36, the most common and longest being isoform 1.<ref name="NCBI" /> Isoform 1 is a kelch-like protein that is 616 amino acids in length with a molecular mass of roughly 70 kilodaltons and an isoelectric point of 5.5.<ref name="nuccore">{{Cite web | title = Homo sapiens kelch like family member 36 (KLHL36), transcript variant 1, mRNA | date = 28 April 2025 | url = https://www.ncbi.nlm.nih.gov/nuccore/NM_024731.4 | access-date = September 11, 2025 }}</ref> The charge of the protein in a neutral environment is -12, with no charge clusters identified.<ref name="cite884e19c5" />
The protein contains a BTB/POZ domain of 135 amino acids at its N-terminus, which is predicted to mediate homodimerization and be involved in cullin 3 binding.<ref name="Zhou_2024" /><ref>{{Cite web | title = kelch-like protein 36 isoform 1 [Homo sapiens] - Protein - NCBI | url = https://www.ncbi.nlm.nih.gov/protein/31542246 | access-date = 2025-09-28 | website = www.ncbi.nlm.nih.gov }}</ref> At its C-terminus, the protein contains 6 Kelch-motif domains which form a β-propeller that is predicted to be involved in substrate binding.<ref>{{cite journal | vauthors = Adams J, Kelso R, Cooley L | title = The kelch repeat superfamily of proteins: propellers of cell function | journal = Trends in Cell Biology | volume = 10 | issue = 1 | pages = 17–24 | date = January 2000 | pmid = 10603472 | doi = 10.1016/S0962-8924(99)01673-6 }}</ref><ref>{{cite journal | vauthors = Dhanoa BS, Cogliati T, Satish AG, Bruford EA, Friedman JS | title = Update on the Kelch-like (KLHL) gene family | journal = Human Genomics | volume = 7 | issue = 1 | date = May 2013 | pmid = 23676014 | pmc = 3658946 | doi = 10.1186/1479-7364-7-13 | doi-access = free | article-number = 13 }}</ref>
There are no unusually scarce or common amino acids present in KLHL36.<ref name="cite884e19c5">{{Cite web | title = PSORT WWW Server | url = https://psort.hgc.jp/ | access-date = 2025-12-11 | website = psort.hgc.jp }}</ref> The secondary structure of the protein is dominated by alpha helices towards the N-terminus in the region of the BTB/POZ Domain and the BACK domain, and by beta sheets towards the C-terminus in the β-propeller domain.<ref>{{Cite web | title = JPred: A Protein Secondary Structure Prediction Server | url = https://www.compbio.dundee.ac.uk/jpred/ | access-date = 2025-12-11 | website = www.compbio.dundee.ac.uk | language = en }}</ref>
Immunofluorescence staining of KLHL36 in the A-549 cell line suggests that the protein localizes to the cytoplasm.<ref>{{Cite web | title = Subcellular - KLHL36 - The Human Protein Atlas | url = https://www.proteinatlas.org/ENSG00000135686-KLHL36/subcellular | access-date = 2025-12-01 | website = www.proteinatlas.org }}</ref> DeepLoc-2.0 analysis of KLHL36 supports this finding, calculating its highest likelihood of subcellular localization to be the cytoplasm at 0.70, followed by the nucleus at 0.48 and the lysosome at 0.25.<ref>{{Cite web | title = DeepLoc 2.0 - DTU Health Tech - Bioinformatic Services | url = https://services.healthtech.dtu.dk/services/DeepLoc-2.0/ | access-date = 2025-12-12 | website = services.healthtech.dtu.dk | language = en }}</ref> Analysis of KLHL36's primary structure reveals no signal peptide, no transmembrane domains, no mitochondrial targeting, no nuclear localization sequence, and no tracking motifs.<ref name="cite884e19c5" />
PhosPhoSite Plus and DTU Health Tech Bioinformatic Services predict many post-translational modifications of KLHL36, including phosphorylation, ubiquitylation, and acetylation.<ref>{{Cite web | title = PhosphoSitePlus | url = https://www.phosphosite.org/homeAction.action | access-date = 2025-12-11 | website = www.phosphosite.org }}</ref><ref>{{Cite web | title = Bioinformatic Tools and Services - DTU Health Tech | url = https://services.healthtech.dtu.dk/ | access-date = 2025-12-11 | website = services.healthtech.dtu.dk }}</ref> These modifications likely contribute to regulating the function of KLHL36 by inducing conformational changes and regulating KLHL36 abundance through ubiquitylation and subsequent proteasomal degradation. == Protein Interactions == Cullin 3 has been shown to directly bind multiple BTB domains through a conserved amino terminal domain.<ref>{{cite journal | vauthors = Furukawa M, He YJ, Borchers C, Xiong Y | title = Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases | journal = Nature Cell Biology | volume = 5 | issue = 11 | pages = 1001–1007 | date = November 2003 | pmid = 14528312 | doi = 10.1038/ncb1056 }}</ref> It is likely that cullin 3 binds the BTB domain present at the N-terminal of KLHL36 to mediate ubiquitylation and degradation of substrate proteins bound by KLHL36. It is not currently known what proteins KLHL36 might bind to facilitate their degradation.
STRING Functional Protein Association Database identifies 10 proteins with which KLHL36 is predicted to interact. These proteins are summarized in '''Table 4'''.<ref>{{Cite web | title = KLHL36 protein (human) - STRING interaction network | url = https://string-db.org/cgi/network?taskId=b9IGjdARSwwf&sessionId=bADaH4Ne6jqp | access-date = 2025-12-11 | website = string-db.org }}</ref> {| class="wikitable" |+'''Table 4.''' STRING Predicted Interaction Partners of ''Homo sapiens'' KLHL36 !Protein !Full Name !Basis for Interaction !Statistical Significance of Basis !Subcellular Localization !Brief Protein Overview |- |CUL3 |Cullin 3 |Co-Expression, Experimental Data, Co-Mentioned in Abstracts |0.049, 0.428, 0.058 |Cytoplasm, nucleoplasm, microtubules, cytokinetic bridge |Component of cullin-RING-based BCR E3 ubiquitin-protein ligase complexes, which mediate ubiquitylation and proteasomal degradation of target proteins. |- |DCLK2 |Serine/threonine-protein kinase, doublecortin like kinase 2 |Experimental Data, Co-Mentioned in Abstracts |0.091, 0.581 |Cytoplasm, microtubules |Part of CaMK protein kinase family that is thought to have reduced affinity and dependence for Ca2+ and CAM compared to other members of the CaMK family. |- |CXorf56 |STING1 ER exit protein 1 |Experimental Data |0.46 |Nucleoplasm, centrosome |Uncharacterized |- |PACRG |Parkin coregulated gene protein |Experimental Data |0.568 |Mitochondria, cilia, flagella |Suppresses cell death induced by accumulation of unfolded Pael receptor. |- |APEX1 |Apurinic/apyrimidinic endodeoxyribonuclease 1 |Experimental Data |0.479 |Nucleoplasm, centrosome |Multifunctional protein thought to play a central role in cellular response to oxidative stress, involved in DNA repair and redox regulation of transcription. |- |KIAA0513 |Uncharacterized protein KIAA0513 |Co-Expression, Co-Mentioned in Abstracts |0.138, 0.522 |Cytosol |Uncharacterized |- |FAM92B/CIBAR2 |CBY1 interacting BAR domain containing 2 |Co-Expression, Co-Mentioned in Abstracts |0.049, 0.448 |Cytoplasm |May play a role in ciliogenesis, cooperates with CBY1 to recruit endosomal vesicles at distal appendages during ciliogenesis. |- |CEP104 |Centrosomal protein of 104 kDa |Co-Expression |0.457 |Centrosome, cytoplasm |Required for ciliogenesis and structural integrity at ciliary tip. |- |TMEM127 |Transmembrane protein 127 |Co-Expression |0.451 |N/A |Negative regulator of TOR signaling pathway that controls cell proliferation, tumor suppressing. |- |SLC15A5 |Solute carrier family 15 member 5 |Co-Mentioned in Abstracts |0.571 |N/A |Proton oligopeptide cotransporter |}
== Clinical Significance == UniProt identifies 770 variants of the KLHL36 gene, with 94 marked as "pathogenic" or "likely pathogenic".<ref name="UniProt_Q8N4N3" /> A single nucleotide polymorphism downstream of KLHL36 (rs12716755) has been reported as a risk variant for early onset Alzheimer's disease.<ref>{{cite journal | vauthors = Stein MB, Choi KW, Jain S, Campbell-Sills L, Chen CY, Gelernter J, He F, Heeringa SG, Maihofer AX, Nievergelt C, Nock MK, Ripke S, Sun X, Kessler RC, Smoller JW, Ursano RJ | title = Genome-wide analyses of psychological resilience in U.S. Army soldiers | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 180 | issue = 5 | pages = 310–319 | date = July 2019 | pmid = 31081985 | pmc = 6551278 | doi = 10.1002/ajmg.b.32730 }}</ref> A genome-wide association study (GWAS) reported an aggregation of 134 single nucleotide polymorphisms implicated in psychological resilience and stress-related psychiatric outcomes in the region of KLHL36 on chromosome 16.<ref>{{cite journal | vauthors = Maul S, Giegling I, Fabbri C, Corponi F, Serretti A, Rujescu D | title = Genetics of resilience: Implications from genome-wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 183 | issue = 2 | pages = 77–94 | date = March 2020 | pmid = 31583809 | doi = 10.1002/ajmg.b.32763 | hdl-access = free | hdl = 11585/793217 }}</ref>
Additionally, transcriptomic analyses have revealed disease-associated changes in KLHL36 expression. KLHL36 mRNA levels have been shown to be lower in gastrointestinal tumors, and increased expression is correlated with positive prognoses in pancreatic cancer and cholangiocarcinoma.<ref>{{cite journal | vauthors = Fu AB, Xiang SF, He QJ, Ying MD | title = Kelch-like proteins in the gastrointestinal tumors | journal = Acta Pharmacologica Sinica | volume = 44 | issue = 5 | pages = 931–939 | date = May 2023 | pmid = 36266566 | pmc = 10104798 | doi = 10.1038/s41401-022-01007-0 }}</ref> Additionally, elevated KLHL36 levels have been associated with reduced tumor proliferation in pancreatic adenocarcinoma models, suggesting a possible tumor suppressor role.<ref>{{cite journal | vauthors = Zhou Y, Huang B, Zhang Q, Yu Y, Xiao J | title = Modeling of new markers for the diagnosis and prognosis of pancreatic cancer based on the transition from inflammation to cancer | journal = Translational Cancer Research | volume = 13 | issue = 3 | pages = 1425–1442 | date = March 2024 | pmid = 38617519 | pmc = 11009810 | doi = 10.21037/tcr-23-1365 | doi-access = free }}</ref> Analyses of triple-negative breast cancer tumors have found that KLHL36 expression can be induced by TNFα stimulation, and that induction of expression can be reversed by the flavonoid apigenin.<ref>{{cite journal | vauthors = Bauer D, Mazzio E, Soliman KF | title = Whole Transcriptomic Analysis of Apigenin on TNFα Immuno-activated MDA-MB-231 Breast Cancer Cells | journal = Cancer Genomics & Proteomics | volume = 16 | issue = 6 | pages = 421–431 | date = 2019 | pmid = 31659097 | pmc = 6885362 | doi = 10.21873/cgp.20146 }}</ref>
KLHL36 has also been implicated in psychiatric contexts. In rodent models, antidepressant treatment and exercise have been negatively correlated with expression of KLHL36 in the brain.<ref>{{cite journal | vauthors = Głombik K, Kukla-Bartoszek M, Suski M, Curzytek K, Grygier B, Basta-Kaim A | title = Comparative effectiveness of moderate treadmill training and venlafaxine treatment on long-lasting brain changes induced by prenatal dexamethasone exposure | journal = Neuropharmacology | volume = 279 | article-number = 110604 | date = November 2025 | pmid = 40738385 | doi = 10.1016/j.neuropharm.2025.110604 | doi-access = free }}</ref> One sequencing analysis found that levels of KLHL36 were significantly increased in both individuals affected by seasonal affective disorder and suicidal ideation.<ref>{{cite journal | vauthors = Han S, DiBlasi E, Monson ET, Shabalin A, Ferris E, Chen D, Fraser A, Yu Z, Staley M, Callor WB, Christensen ED, Crockett DK, Li QS, Willour V, Bakian AV, Keeshin B, Docherty AR, Eilbeck K, Coon H | title = Whole-genome sequencing analysis of suicide deaths integrating brain-regulatory eQTLs data to identify risk loci and genes | journal = Molecular Psychiatry | volume = 28 | issue = 9 | pages = 3909–3919 | date = September 2023 | pmid = 37794117 | pmc = 10730410 | doi = 10.1038/s41380-023-02282-x }}</ref>
== References == {{reflist}}
Category:Proteins